VCV000065758.116 - ClinVar

NM_145239.3(PRRT2):c.649dup (p.Arg217fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(72)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_145239.3(PRRT2):c.649dup (p.Arg217fs)

Variation ID: 65758 Accession: VCV000065758.116

Type and length

Duplication, 1 bp

Location

Cytogenetic: 16p11.2 16: 29813694-29813695 (GRCh38) [ NCBI UCSC ] 16: 29825015-29825016 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 17, 2013	Oct 26, 2024	Oct 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_145239.3:c.640_641insC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_145239.3:c.649dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_660282.2:p.Arg217fs	frameshift
NM_145239.3:c.649dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001256442.1:c.649dup
NM_001256442.2:c.649dup	NP_001243371.1:p.Arg217fs	frameshift
NM_001256443.2:c.649dup	NP_001243372.1:p.Arg217fs	frameshift
NM_145239.2:c.649_650insC
NC_000016.10:g.29813703dup
NC_000016.9:g.29825024dup
NG_032039.1:g.6616dup

... more HGVS ... less HGVS

Protein change

R217fs

Other names

p.Arg217ProfsTer8
649_650insC

Canonical SPDI

NC_000016.10:29813694:CCCCCCCCC:CCCCCCCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA180353 OMIM: 614386.0001 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PRRT2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	8	904
MVP-DT	-	-	-	GRCh38	-	757

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Episodic kinesigenic dyskinesia 1	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Jul 25, 2024	RCV000055991.43
Infantile convulsions and choreoathetosis	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Oct 1, 2024	RCV000153783.39
not provided	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000188779.60
Seizure	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 5, 2024	RCV000193894.18
Paroxysmal nonkinesigenic dyskinesia 1	Pathogenic (1)	criteria provided, single submitter	Jun 17, 2019	RCV000991298.9
Episodic kinesigenic dyskinesia 1 Infantile convulsions and choreoathetosis Seizures, benign familial infantile, 2	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2022	RCV000768059.10
Seizures, benign familial infantile, 2	Pathogenic/Likely pathogenic (13)	criteria provided, multiple submitters, no conflicts	Feb 16, 2023	RCV000585818.45
PRRT2 insufficiency	Pathogenic (1)	criteria provided, single submitter	Mar 1, 2020	RCV001264813.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 7, 2023	RCV002313738.9
Self-limited familial infantile epilepsy	Pathogenic (1)	criteria provided, single submitter	Jul 17, 2023	RCV002470742.9
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002273952.9
Episodic kinesigenic dyskinesia	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000791409.15
PRRT2-Associated Paroxysmal Movement Disorders	Pathogenic (1)	criteria provided, single submitter	Mar 26, 2021	RCV001563615.12
See cases	Pathogenic (1)	criteria provided, single submitter	Aug 24, 2022	RCV004584342.1
PRRT2-related disorder	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 15, 2022	RCV002280097.12
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 05, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HP:0001250 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000248604.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Jan 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: unknown	NeuroMeGen, Hospital Clinico Santiago de Compostela Accession: SCV000693768.1 First in ClinVar: Mar 11, 2018 Last updated: Mar 11, 2018	Observation 1: Observation 2:
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140084.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Jun 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paroxysmal nonkinesigenic dyskinesia 1 Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV001142699.1 First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020	Publications: PubMed (2) PubMed: 22101681‚ 26598493 Number of individuals with the variant: 3
Pathogenic (Mar 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164215.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164113.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Sep 06, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV001167610.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Sex: male Secondary finding: no
Pathogenic (Nov 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001192520.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020	Comment: ACMG codes: PVS1, PM1, PP1, PP5 Number of individuals with the variant: 1 Clinical Features: Intrauterine growth retardation (present) , Small for gestational age (present) , Birth length less than 3rd percentile (present) , Anemia (present) , Cardiomyopathy (present) , … (more) Intrauterine growth retardation (present) , Small for gestational age (present) , Birth length less than 3rd percentile (present) , Anemia (present) , Cardiomyopathy (present) , Congenital microcephaly (present) , Abnormality of blood and blood-forming tissues (present) , Hearing impairment (present) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001244945.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368515.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM1,PP5.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizure Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737060.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 Comment: Homozygous, both variants are inherited from each parent
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737112.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Jun 05, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001760953.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Publications: PubMed (3) PubMed: 29334453‚ 26598493‚ 24370076 Comment: The inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is the duplication of a single nucleotide, resulting in the frameshift and premature termination of … (more) The inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is the duplication of a single nucleotide, resulting in the frameshift and premature termination of the protein approximately 8 amino acids downstream (coding exon 2/4). This variant is found in 21 heterozygous individuals in gnomAD(v3.0), with an allele frequency of 1.49e-4. This variant is reported in ClinVar as Pathogenic (VarID:65758), and is the most common pathogenic PRRT2 variant identified in affected individuals [PMID:29334453; PMID:26598493; PMID:24370076]. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID:25457817]. Given this, the inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is reported as Pathogenic. (less) Clinical Features: Seizure (present) Secondary finding: no
Pathogenic (Mar 26, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	PRRT2-Associated Paroxysmal Movement Disorders Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001786591.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Publications: PubMed (6) PubMed: 22101681‚ 22243967‚ 22399141‚ 22832103‚ 23299620‚ 26598493 Comment: The PRRT2 c.649dupC (p.Arg217ProfsTer8) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. Across a selection … (more) The PRRT2 c.649dupC (p.Arg217ProfsTer8) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. Across a selection of the available literature, the p.Arg217ProfsTer8 variant has been identified in approximately 78% of all 1444 individuals with published PRRT2 variants (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Lee et al. 2012; Becker et al. 2013; Ebrahimi-Fakhari et al. 2015). The phenotype of affected individuals includes paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions and choreoathetosis. The p.Arg217ProfsTer8 variant was found to segregate with disease in many familial cases with high penetrance, although incomplete penetrance in several families has been described (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Becker et al. 2013). The p.Arg217ProfsTer8 variant is reported at a frequency of 0.0001727 in the African/African-American population of the Genome Aggregation Database. PRRT2 is a transmembrane protein, and the p.Arg217ProfsTer8 variant is expected to disrupt the transmembrane domain (Chen et al. 2011). Functional studies demonstrated absence of this truncated protein in transfected cell lines and cultured hippocampal neurons (Lee et al. 2012). Co-transfection of p.Arg217ProfsTer8 with wild-type PRRT2 demonstrated normal expression of wild-type PRRT2 and low/undetectable expression of truncated PRRT2, suggesting haploinsufficiency as the disease mechanism (Lee et al. 2012). Based on the collective evidence and application of ACMG criteria, the variant is classified as pathogenic for PRRT2-associated paroxysmal movement disorders. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: paternal	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001554493.2 First in ClinVar: Apr 13, 2021 Last updated: Mar 01, 2022	Publications: PubMed (1) PubMed: 34782754
Pathogenic (Jun 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PRRT2-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568212.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PVS1, PS4, PP1
Pathogenic (Jan 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577560.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PVS1, PS3, PP5
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818270.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242403.12 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014); Frameshift variant predicted to … (more) Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene; This variant is associated with the following publications: (PMID: 25522171, 23180180, 25502464, 23535490, 22877996, 22782515, 24661410, 22744660, 24370076, 27959697, 30182498, 30034362, 29250726, 31785815, 31901402, 31302675, 29655203, 26876767, 22101681, 25595153, 22243967, 23768507, 24074546, 22845787, 23771590, 23182655, 23126439, 24609974, 23532549, 22870186, 22623405, 27920401, 25915028, 27123484, 27172900, 28553402, 28097321, 28566192, 28525812, 29215089, 29778030, 29852413, 28018471, 29285950, 29302074, 30501978, 29132464, 30392205, 30125676, 30847922, 30814447, 31780880, 31737037, 31154286, 31722684, 32002278, 31216405, 32246320, 33126500, 34489640, 34298454, 32651081, 33391346, 33327426, 32613771, 33043084, 33258288, 32964447, 25667652, 25457817, 32860008, 33726816, 32237035) (less)
Pathogenic (Jun 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004020389.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (2) PubMed: 33661484‚ 25457817 Comment: Variant summary: PRRT2 c.649dupC (p.Arg217ProfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: PRRT2 c.649dupC (p.Arg217ProfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0037 in 135540 control chromosomes, however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.649dupC has been reported in the literature in multiple individuals affected with PRRT2-related conditions (e.g., Ji_2021). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33661484, 25457817). 39 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: paternal	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004042676.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PRRT2-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046274.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more) This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant is a recurrent cause of benign familial infantile epilepsy, infantile convulsions and choreoathetosis, and paroxysmal kinesigenic dyskinesia (PMID: 23299620, 22101681, 22870186, 22877996, 25667652). The c.649dup (p.Arg217ProfsTer8) variant is present in the gnomAD population database at a frequency of 0.3% (514/165666); however, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, the c.649dup (p.Arg217ProfsTer8) variant is classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004046802.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023
Pathogenic (Mar 06, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000614795.5 First in ClinVar: Dec 06, 2016 Last updated: Jan 26, 2024	Publications: PubMed (20) PubMed: 22870186‚ 23077017‚ 23077026‚ 22131361‚ 23077024‚ 22875091‚ 22209761‚ 24370076‚ 23771590‚ 25522171‚ 25502464‚ 22101681‚ 22243967‚ 22782515‚ 23126439‚ 23182655‚ 22120146‚ 22623405‚ 22399141‚ 11179027 Comment: This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population appears higher than … (more) This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population appears higher than would generally be expected for pathogenic variants in this gene, however, the data have failed quality metrics and thus are not useful in evaluating the pathogenicity of this variant (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has not been reported in control populations composed of more than 4,000 samples and varying ethnicities, which is consistent with the pathogenicity of this variant (PMID: 22243967, 22870186, 22875091, 23077024, 23077026, 22399141, 22209761, 22101681, 22131361, 25522171). This variant associates with various PRRT2-related disorders in multiple families, and is also reported to have reduced penetrance and variable expression between and within families (PMID: 23077026, 22782515, 23126439, 22120146, 22623405, 23077017, 23182655, 23771590, 24370076, 25502464). This variant appears to occur de novo in multiple individuals with various PRRT2-related disorders (PMID: 23077026, 22399141). (less)
Pathogenic (Apr 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019531.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Episodic kinesigenic dyskinesia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291481.11 First in ClinVar: Jul 30, 2015 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 28492532‚ 22623405‚ 22744660‚ 22101681‚ 22870186‚ 22877996‚ 23299620‚ 25667652 Comment: This sequence change creates a premature translational stop signal (p.Arg217Profs8) in the PRRT2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg217Profs8) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (PMID: 22101681, 22870186, 22877996, 23299620, 25667652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65758). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428611.10 First in ClinVar: Aug 15, 2020 Last updated: Apr 15, 2024	Comment: Criteria applied: PVS1,PS3 Clinical Features: Hydronephrosis (present) , Seizure (present) , Congenital megaureter (present) Sex: male
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000849074.6 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 22101681‚ 22243967‚ 22832103‚ 24928127‚ 25457817‚ 25915028‚ 26598493 Comment: The c.649dupC (p.R217Pfs8) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, results from a duplication of C at position 649, causing … (more) The c.649dupC (p.R217Pfs8) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, results from a duplication of C at position 649, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.649dupC allele has an overall frequency of 0.31% (514/165666) total alleles studied. The highest observed frequency was 0.47% (22/4682) of Ashkenazi Jewish alleles. The PRRT2 c.649dupC (p.R217Pfs8) alteration is the most common pathogenic variant in PRRT2 and can be identified in approximately 80% of affected individuals (Ebrahimi-Fakhari, 2015). This alteration has been identified in individuals and families with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, or a combination of these presentations (Chen, 2011; Heron, 2012; Pelzer, 2014; Ebrahimi-Fakhari, 2015). Functional analysis demonstrated that the PRRT2 c.649dupC (p.R217Pfs8) alteration results in an mRNA transcript that undergoes nonsense mediated decay (Wu, 2014). Any truncated mRNA transcript that is translated has been shown to mislocalize and is found in the cytoplasm rather than the plasma membrane (Chen, 2011). Other studies have found no detectable protein associated with the c.649dupC (p.R217Pfs8) alteration (Li, 2015). Functional studies have also shown that the c.649dupC (p.R217Pfs8) alteration results in a protein that is unable to interact with components of the SNARE complex or glutamate receptors (Li, 2015). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV005040954.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Sex: male
Pathogenic (Aug 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002578007.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PVS1,PS4,PP3,PP5,BS1 Number of individuals with the variant: 1 Clinical Features: Seizure (present) Age: 0-9 years Sex: female Tissue: blood
Pathogenic (Jan 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197281.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jul 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001251443.2 First in ClinVar: May 31, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4,PS3_SUP Clinical Features: Hyperkinetic movements (present) , Dystonic disorder (present) , Divergence nystagmus (present) Sex: male
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248447.25 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PRRT2: PVS1, PP1:Strong, PS2, PS4:Moderate Number of individuals with the variant: 91
Pathogenic (Oct 23, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281646.1 First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016
Pathogenic (Jul 23, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Episodic kinesigenic dyskinesia 1 Seizures, benign familial infantile, 2 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898913.1 First in ClinVar: Apr 25, 2019 Last updated: Apr 25, 2019	Comment: PRRT2 NM_145239.2 exon 2 p.Arg217Profs8 (c.649dupC): This variant has been well reported in the literature (including an entry in GeneReviews) and has been identified in … (more) PRRT2 NM_145239.2 exon 2 p.Arg217Profs8 (c.649dupC): This variant has been well reported in the literature (including an entry in GeneReviews) and has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members (Chen 2011 PMID:22101681, Dale 2012 PMID:22845787, Heron 2012 PMID:22243967, Castiglioni 2013 PMID:23182655, He 2014 PMID:25522171, Ebrahimi-Fakhari 2015 PMID:26598493, Ebrahimi-Fakhari 2018 PMID:29334453). In addition, a review article suggests that this variant may account for 78.5% of the reported cases in the literature (Ebrahimi-Fakhari 2015 PMID:26598493). This variant is present in 8/29718 alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772994486). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:65758). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an addition of 1 nucleotide within a string of cytosines at position 649 and creates a premature stop codon 8 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Ebrahimi-Fakhari 2015 PMID:26598493). In summary, this variant is classified as pathogenic . (less)
Pathogenic (Apr 29, 2014)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000203360.5 First in ClinVar: Jan 29, 2015 Last updated: Jul 31, 2019	Publications: PubMed (3) PubMed: 22101681‚ 23180180‚ 23182655 Number of individuals with the variant: 6 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426446.1 First in ClinVar: Aug 06, 2020 Last updated: Aug 06, 2020
Pathogenic (Mar 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PRRT2 insufficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443008.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2, PM3; observed in two families Clinical Features: severe ID (present) , seizures (present) , bruxism (present) , self-mutilation (present)
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905656.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Clinical Features: Seizure (present) , Epileptic spasm (present) Sex: male
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: paternal	3billion Accession: SCV002012092.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Comment: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more) Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of [0.003103. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000065758.42, PS4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Seizure (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Gray matter heterotopia (present)
Pathogenic (Aug 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059398.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: yes Allele origin: germline	DASA Accession: SCV002061239.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (4) PubMed: 22101681‚ 22870186‚ 22877996‚ 25667652 Comment: The c.649dup;p.(Arg217Profs8) is a null frameshift variant (NMD) in the PRRT2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more) The c.649dup;p.(Arg217Profs8) is a null frameshift variant (NMD) in the PRRT2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65758; PMID: 22101681; 22870186; 22877996; 25667652) - PS4 and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental delay Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559023.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581620.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3, PS4, PP1	Number of individuals with the variant: 5 Sex: male
Pathogenic (Mar 07, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal, maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149892.2 First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: Dystonic disorder (present) , Dyskinesia (present) , Myoclonus (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Muscle weakness (present) , Seizure (present) , Migraine (present) Observation 3: Number of individuals with the variant: 1 Clinical Features: Bilateral tonic-clonic seizure (present) , Patent foramen ovale (present) Observation 4: Number of individuals with the variant: 1 Clinical Features: Paroxysmal dyskinesia (present) , Dystonic disorder (present)
Pathogenic (Jan 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 Infantile convulsions and choreoathetosis Seizures, benign familial infantile, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002792003.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003842254.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (1) PubMed: 22101681 Comment: A Heterozygous Frameshift variant c.640_641insC in Exon 2 of the PRRT2 gene that results in the amino acid substitution p.Arg217fs8 was identified. The observed variant … (more) A Heterozygous Frameshift variant c.640_641insC in Exon 2 of the PRRT2 gene that results in the amino acid substitution p.Arg217fs8 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (Variant ID: 65758). This variant has been identified in patients with infantile choreoathetosis and paroxysmal kinesigenic dyskinesia (Chen WJ et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Seizures, benign familial infantile, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Pediatrics, Sichuan Provincial Hospital For Women And Children Accession: SCV003842214.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: The proband, a male, 9 months old, There was no obvious cause before the onset of convulsion, the form of Generalized tonic-clonic seizures (GTCS), which … (more) The proband, a male, 9 months old, There was no obvious cause before the onset of convulsion, the form of Generalized tonic-clonic seizures (GTCS), which occurred about 1-2 minutes after spontaneous stop.His mother and grandfather had the same seizure up to the age of six years old, after which they healed (less) Clinical Features: Seizure (present) Age: 0-9 years Comment on evidence: ACGM classified this mutation as likely pathogenic (PVS1+PP1+PP3) Testing laboratory: Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Hospital for Women and Children
Pathogenic (Dec 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807085.2 First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PM6 moderated, PP1 strong, BS1 strong Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004101501.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Comment: The frameshift c.649dup (p.Arg217ProfsTer8) variant has been reported previously in heterozygous state in patients affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Swoboda KJ. et. … (more) The frameshift c.649dup (p.Arg217ProfsTer8) variant has been reported previously in heterozygous state in patients affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Swoboda KJ. et. al., 2000; Lee HY et. al., 2012).This position has been reported to be a mutational hotspot (Mao CY et. al., 2014) and as such, this variant is considered one of the most common, recurrent causes of both PKD and benign familial infantile seizures (Steinlein OK et. al., 2012; Becker F et. al., 2013). The p.Arg217ProfsTer8 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This mutation creates a premature translational stop signal (p.Arg217Profs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Bilateral tonic-clonic seizure (present) , EEG abnormality (present) , Lactic acidosis (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042834.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The frameshift variant c.649dupp.Arg217ProfsTer8 in PRRT2 gene has been reported previously in heterozygous state in individuals affected with benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and … (more) The frameshift variant c.649dupp.Arg217ProfsTer8 in PRRT2 gene has been reported previously in heterozygous state in individuals affected with benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia Wang Y, et al., 2017, Zheng W, et al., 2016. Experimental studies indicate that this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014. The variant is reported with 0.3% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic multiple submissions. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715149.3 First in ClinVar: Jun 15, 2021 Last updated: Jun 02, 2024	Comment: PVS1, PS3, PS4, PP1, PP5 Number of individuals with the variant: 7
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures, benign familial infantile, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820154.4 First in ClinVar: Jan 21, 2023 Last updated: Jul 15, 2024	Comment: The observed frameshift c.649dup(p.Arg217ProfsTer8) variant in PRRT2 gene has been reported previously in heterozygous state in individual(s) affected with infantile seizures and/or paroxysmal kinesigenic dyskinesia … (more) The observed frameshift c.649dup(p.Arg217ProfsTer8) variant in PRRT2 gene has been reported previously in heterozygous state in individual(s) affected with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (Steinlein et al., 2012; Chen GH., 2015). This variant is reported with the allele frequency of 0.4% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (Méneret et al., 2012). For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Self-limited familial infantile epilepsy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767234.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 22101681‚ 25502464‚ 26561923‚ 29334453 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial infantile convulsions with paroxysmal choreoathetosis (MIM#602066), episodic kinesigenic dyskinesia 1 (MIM#128200), benign familial infantile seizures 2 (MIM#605751) and self-limited familial and non-familial infantile seizures (MONDO#0100024). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for paroxysmal kinesigenic dyskinesia (PMID: 29334453). (I) 0115 - Variants in this gene are known to have variable expressivity. Variation in phenotype has been reported within and between families with the same pathogenic variant (PMID: 29334453). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (514 heterozygotes, 0 homozygotes; variant did not pass quality filter). (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, PMIDs: 22101681, 26561923, 25502464). (SP) 0901 - This variant has strong evidence for segregation with disease (PMIDs: 22101681, 25502464). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088752.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene. The variant has been identified … (more) This variant is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene. The variant has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members [PMID: 22101681, 22845787, 22243967, 23182655, 25522171, 26598493, 29334453]. It has also been reported to have reduced penetrance and variable expression between and within families. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID: 25457817]. (less)
Pathogenic (Oct 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368156.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4 Clinical Features: Seizure (present) , Neurodevelopmental delay (present) Sex: female
Pathogenic (May 01, 2016)	no assertion criteria provided Method: clinical testing	Episodic kinesigenic dyskinesia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Baylor Genetics Accession: SCV000328734.1 First in ClinVar: Jul 30, 2015 Last updated: Jul 30, 2015	Publications: PubMed (6) PubMed: 22101681‚ 22243967‚ 22782515‚ 23768507‚ 24074546‚ 22845787 Comment: Our laboratory reported two molecular diagnoses in KCNQ2 (NM_172108.4, c.2332delC) and PRRT2 (NM_145239.2, c.649dup) in an individual with Ohtahara syndrome, severe developmental delay, seizure disorder, … (more) Our laboratory reported two molecular diagnoses in KCNQ2 (NM_172108.4, c.2332delC) and PRRT2 (NM_145239.2, c.649dup) in an individual with Ohtahara syndrome, severe developmental delay, seizure disorder, structural brain anomalies and eye anomalies, severe hypotonia, bilateral hearing loss, and dysmorphic features. (less)
Pathogenic (Jun 07, 2020)	no assertion criteria provided Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469261.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045456.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (6) PubMed: 22101681‚ 22120146‚ 22243967‚ 22744660‚ 22623405‚ 22399141 Comment on evidence: In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) … (more) In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and introduction of a stop codon 7 amino acids downstream of the insertion (Arg217ProfsTer8). The mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The mutation completely segregated with the phenotype in each family and was not found in unaffected family members. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. A 189-kb common haplotype flanking the mutation was found in 3 of the families, a second different haplotype was found in 2 other families, and a third haplotype was found in the third family. Clinical features of the proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution. Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1, Wang et al. (2011) independently and simultaneously identified a heterozygous 649dupC mutation in the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a truncated protein containing only 223 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation. The mutation was not found in 500 controls. There was some phenotypic variability: the first family had dystonia, choreoathetosis or athetosis, the second family had predominant dystonia of the upper limbs, whereas the third had predominant dystonia of the lower limbs. In affected members of 3 unrelated families with familial infantile convulsions with paroxysmal choreoathetosis, Heron et al. (2012) identified a heterozygous 649dupC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649dupC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. There was no evidence of a common haplotype among these families. The PRRT2 649dupC mutation clearly occurs at a mutation hotspot, and occurs in a homopolymer of 9 C bases adjacent to 4 G bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication. Meneret et al. (2012) found that the 649dupC mutation was the most common mutation in a cohort of patients of European descent with EKD1/ICCA. The mutation was present in 17 of 22 patients with PRRT2 mutations. Several unaffected family members also carried the mutation, indicating incomplete penetrance. There were at least 5 different haplotypes with the mutation, and it was found to occur de novo in 2 patients, indicating that it is a mutation hotspot. Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). The patients were of German, Italian, Japanese, and Turkish origin. The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance. Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. (less)
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	EPISODIC KINESIGENIC DYSKINESIA 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045455.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (6) PubMed: 22101681‚ 22120146‚ 22243967‚ 22744660‚ 22623405‚ 22399141 Comment on evidence: In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) … (more) In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and introduction of a stop codon 7 amino acids downstream of the insertion (Arg217ProfsTer8). The mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The mutation completely segregated with the phenotype in each family and was not found in unaffected family members. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. A 189-kb common haplotype flanking the mutation was found in 3 of the families, a second different haplotype was found in 2 other families, and a third haplotype was found in the third family. Clinical features of the proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution. Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1, Wang et al. (2011) independently and simultaneously identified a heterozygous 649dupC mutation in the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a truncated protein containing only 223 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation. The mutation was not found in 500 controls. There was some phenotypic variability: the first family had dystonia, choreoathetosis or athetosis, the second family had predominant dystonia of the upper limbs, whereas the third had predominant dystonia of the lower limbs. In affected members of 3 unrelated families with familial infantile convulsions with paroxysmal choreoathetosis, Heron et al. (2012) identified a heterozygous 649dupC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649dupC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. There was no evidence of a common haplotype among these families. The PRRT2 649dupC mutation clearly occurs at a mutation hotspot, and occurs in a homopolymer of 9 C bases adjacent to 4 G bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication. Meneret et al. (2012) found that the 649dupC mutation was the most common mutation in a cohort of patients of European descent with EKD1/ICCA. The mutation was present in 17 of 22 patients with PRRT2 mutations. Several unaffected family members also carried the mutation, indicating incomplete penetrance. There were at least 5 different haplotypes with the mutation, and it was found to occur de novo in 2 patients, indicating that it is a mutation hotspot. Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). The patients were of German, Italian, Japanese, and Turkish origin. The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance. Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. (less)
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	SEIZURES, BENIGN FAMILIAL INFANTILE, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045457.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024	Publications: PubMed (6) PubMed: 22101681‚ 22120146‚ 22243967‚ 22744660‚ 22623405‚ 22399141 Comment on evidence: In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) … (more) In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and introduction of a stop codon 7 amino acids downstream of the insertion (Arg217ProfsTer8). The mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The mutation completely segregated with the phenotype in each family and was not found in unaffected family members. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. A 189-kb common haplotype flanking the mutation was found in 3 of the families, a second different haplotype was found in 2 other families, and a third haplotype was found in the third family. Clinical features of the proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution. Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1, Wang et al. (2011) independently and simultaneously identified a heterozygous 649dupC mutation in the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a truncated protein containing only 223 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation. The mutation was not found in 500 controls. There was some phenotypic variability: the first family had dystonia, choreoathetosis or athetosis, the second family had predominant dystonia of the upper limbs, whereas the third had predominant dystonia of the lower limbs. In affected members of 3 unrelated families with familial infantile convulsions with paroxysmal choreoathetosis, Heron et al. (2012) identified a heterozygous 649dupC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649dupC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. There was no evidence of a common haplotype among these families. The PRRT2 649dupC mutation clearly occurs at a mutation hotspot, and occurs in a homopolymer of 9 C bases adjacent to 4 G bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication. Meneret et al. (2012) found that the 649dupC mutation was the most common mutation in a cohort of patients of European descent with EKD1/ICCA. The mutation was present in 17 of 22 patients with PRRT2 mutations. Several unaffected family members also carried the mutation, indicating incomplete penetrance. There were at least 5 different haplotypes with the mutation, and it was found to occur de novo in 2 patients, indicating that it is a mutation hotspot. Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). The patients were of German, Italian, Japanese, and Turkish origin. The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance. Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. (less)
Pathogenic (Sep 04, 2024)	no assertion criteria provided Method: clinical testing	PRRT2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004774144.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The PRRT2 c.649dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Profs8). This variant has previously been reported to be causative … (more) The PRRT2 c.649dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Profs8). This variant has previously been reported to be causative for a broad range of autosomal dominant PRRT2-related phenotypes such as paroxysmal kinesigenic dyskinesia, familial hemiplegic migraine, benign familial infantile epilepsy (BFIE), and paroxysmal torticollis (Chen et al. 2011. PubMed ID: 22101681; Li et al. 2013. PubMed ID: 23535490; Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493; Zhao et al. 2018. PubMed ID: 29285950). In addition to variable expressivity, reduced penetrance is also documented for this gene (Ebrahimi-Fakhari et al. 1993. PubMed ID: 29334453). The c.649dup is the most common pathogenic variant reported in the PRRT2 gene. Note that allele frequency estimates at this position in the gnomAD public population database may be inaccurate. In summary, we classify this variant as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807268.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931576.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (Jun 21, 2021)	no assertion criteria provided Method: clinical testing	Seizures, benign familial infantile, 2 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002011753.1 First in ClinVar: Nov 05, 2021 Last updated: Nov 05, 2021
Pathogenic (Oct 25, 2021)	no assertion criteria provided Method: clinical testing	Infantile convulsions and choreoathetosis Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002029206.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036777.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (Jun 02, 2022)	no assertion criteria provided Method: clinical testing	Episodic kinesigenic dyskinesia 1 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583481.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Episodic kinesigenic dyskinesia 1 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005199990.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team Number of individuals with the variant: 2
not provided (-)	no classification provided Method: literature only	Episodic kinesigenic dyskinesia 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000087045.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (6) PubMed: 29334453‚ 26598493‚ 22101681‚ 22120146‚ 22131361‚ 22209761 BookShelf: NBK475803 BookShelf: NBK475803
not provided (-)	no classification provided Method: literature only	Infantile convulsions and choreoathetosis Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000747727.2 First in ClinVar: Jul 30, 2015 Last updated: Oct 01, 2022	Publications: PubMed (6) PubMed: 29334453‚ 26598493‚ 22101681‚ 22120146‚ 22131361‚ 22209761 BookShelf: NBK475803 BookShelf: NBK475803
not provided (-)	no classification provided Method: literature only	Seizures, benign familial infantile, 2 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000747728.2 First in ClinVar: Mar 11, 2018 Last updated: Oct 01, 2022	Publications: PubMed (6) PubMed: 29334453‚ 26598493‚ 22101681‚ 22120146‚ 22131361‚ 22209761 BookShelf: NBK475803 BookShelf: NBK475803
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Comment:

The inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is the duplication of a single nucleotide, resulting in the frameshift and premature termination of the protein approximately 8 amino acids downstream (coding exon 2/4). This variant is found in 21 heterozygous individuals in gnomAD(v3.0), with an allele frequency of 1.49e-4. This variant is reported in ClinVar as Pathogenic (VarID:65758), and is the most common pathogenic PRRT2 variant identified in affected individuals [PMID:29334453; PMID:26598493; PMID:24370076]. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID:25457817]. Given this, the inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is reported as Pathogenic.

Comment:

The PRRT2 c.649dupC (p.Arg217ProfsTer8) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. Across a selection of the available literature, the p.Arg217ProfsTer8 variant has been identified in approximately 78% of all 1444 individuals with published PRRT2 variants (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Lee et al. 2012; Becker et al. 2013; Ebrahimi-Fakhari et al. 2015). The phenotype of affected individuals includes paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions and choreoathetosis. The p.Arg217ProfsTer8 variant was found to segregate with disease in many familial cases with high penetrance, although incomplete penetrance in several families has been described (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Becker et al. 2013). The p.Arg217ProfsTer8 variant is reported at a frequency of 0.0001727 in the African/African-American population of the Genome Aggregation Database. PRRT2 is a transmembrane protein, and the p.Arg217ProfsTer8 variant is expected to disrupt the transmembrane domain (Chen et al. 2011). Functional studies demonstrated absence of this truncated protein in transfected cell lines and cultured hippocampal neurons (Lee et al. 2012). Co-transfection of p.Arg217ProfsTer8 with wild-type PRRT2 demonstrated normal expression of wild-type PRRT2 and low/undetectable expression of truncated PRRT2, suggesting haploinsufficiency as the disease mechanism (Lee et al. 2012). Based on the collective evidence and application of ACMG criteria, the variant is classified as pathogenic for PRRT2-associated paroxysmal movement disorders.

Comment:

Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene; This variant is associated with the following publications: (PMID: 25522171, 23180180, 25502464, 23535490, 22877996, 22782515, 24661410, 22744660, 24370076, 27959697, 30182498, 30034362, 29250726, 31785815, 31901402, 31302675, 29655203, 26876767, 22101681, 25595153, 22243967, 23768507, 24074546, 22845787, 23771590, 23182655, 23126439, 24609974, 23532549, 22870186, 22623405, 27920401, 25915028, 27123484, 27172900, 28553402, 28097321, 28566192, 28525812, 29215089, 29778030, 29852413, 28018471, 29285950, 29302074, 30501978, 29132464, 30392205, 30125676, 30847922, 30814447, 31780880, 31737037, 31154286, 31722684, 32002278, 31216405, 32246320, 33126500, 34489640, 34298454, 32651081, 33391346, 33327426, 32613771, 33043084, 33258288, 32964447, 25667652, 25457817, 32860008, 33726816, 32237035)

Comment:

Variant summary: PRRT2 c.649dupC (p.Arg217ProfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0037 in 135540 control chromosomes, however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.649dupC has been reported in the literature in multiple individuals affected with PRRT2-related conditions (e.g., Ji_2021). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33661484, 25457817). 39 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant is a recurrent cause of benign familial infantile epilepsy, infantile convulsions and choreoathetosis, and paroxysmal kinesigenic dyskinesia (PMID: 23299620, 22101681, 22870186, 22877996, 25667652). The c.649dup (p.Arg217ProfsTer8) variant is present in the gnomAD population database at a frequency of 0.3% (514/165666); however, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, the c.649dup (p.Arg217ProfsTer8) variant is classified as Pathogenic.

Comment:

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population appears higher than would generally be expected for pathogenic variants in this gene, however, the data have failed quality metrics and thus are not useful in evaluating the pathogenicity of this variant (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has not been reported in control populations composed of more than 4,000 samples and varying ethnicities, which is consistent with the pathogenicity of this variant (PMID: 22243967, 22870186, 22875091, 23077024, 23077026, 22399141, 22209761, 22101681, 22131361, 25522171). This variant associates with various PRRT2-related disorders in multiple families, and is also reported to have reduced penetrance and variable expression between and within families (PMID: 23077026, 22782515, 23126439, 22120146, 22623405, 23077017, 23182655, 23771590, 24370076, 25502464). This variant appears to occur de novo in multiple individuals with various PRRT2-related disorders (PMID: 23077026, 22399141).

Comment:

This sequence change creates a premature translational stop signal (p.Arg217Profs*8) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (PMID: 22101681, 22870186, 22877996, 23299620, 25667652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65758). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.649dupC (p.R217Pfs*8) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, results from a duplication of C at position 649, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.649dupC allele has an overall frequency of 0.31% (514/165666) total alleles studied. The highest observed frequency was 0.47% (22/4682) of Ashkenazi Jewish alleles. The PRRT2 c.649dupC (p.R217Pfs*8) alteration is the most common pathogenic variant in PRRT2 and can be identified in approximately 80% of affected individuals (Ebrahimi-Fakhari, 2015). This alteration has been identified in individuals and families with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, or a combination of these presentations (Chen, 2011; Heron, 2012; Pelzer, 2014; Ebrahimi-Fakhari, 2015). Functional analysis demonstrated that the PRRT2 c.649dupC (p.R217Pfs*8) alteration results in an mRNA transcript that undergoes nonsense mediated decay (Wu, 2014). Any truncated mRNA transcript that is translated has been shown to mislocalize and is found in the cytoplasm rather than the plasma membrane (Chen, 2011). Other studies have found no detectable protein associated with the c.649dupC (p.R217Pfs*8) alteration (Li, 2015). Functional studies have also shown that the c.649dupC (p.R217Pfs*8) alteration results in a protein that is unable to interact with components of the SNARE complex or glutamate receptors (Li, 2015). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

PRRT2 NM_145239.2 exon 2 p.Arg217Profs*8 (c.649dupC): This variant has been well reported in the literature (including an entry in GeneReviews) and has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members (Chen 2011 PMID:22101681, Dale 2012 PMID:22845787, Heron 2012 PMID:22243967, Castiglioni 2013 PMID:23182655, He 2014 PMID:25522171, Ebrahimi-Fakhari 2015 PMID:26598493, Ebrahimi-Fakhari 2018 PMID:29334453). In addition, a review article suggests that this variant may account for 78.5% of the reported cases in the literature (Ebrahimi-Fakhari 2015 PMID:26598493). This variant is present in 8/29718 alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772994486). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:65758). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an addition of 1 nucleotide within a string of cytosines at position 649 and creates a premature stop codon 8 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Ebrahimi-Fakhari 2015 PMID:26598493). In summary, this variant is classified as pathogenic .

Comment:

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of [0.003103. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000065758.42, PS4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The c.649dup;p.(Arg217Profs*8) is a null frameshift variant (NMD) in the PRRT2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65758; PMID: 22101681; 22870186; 22877996; 25667652) - PS4 and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

A Heterozygous Frameshift variant c.640_641insC in Exon 2 of the PRRT2 gene that results in the amino acid substitution p.Arg217fs*8 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (Variant ID: 65758). This variant has been identified in patients with infantile choreoathetosis and paroxysmal kinesigenic dyskinesia (Chen WJ et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

Comment:

The proband, a male, 9 months old, There was no obvious cause before the onset of convulsion, the form of Generalized tonic-clonic seizures (GTCS), which occurred about 1-2 minutes after spontaneous stop.His mother and grandfather had the same seizure up to the age of six years old, after which they healed

Comment:

The frameshift c.649dup (p.Arg217ProfsTer8) variant has been reported previously in heterozygous state in patients affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Swoboda KJ. et. al., 2000; Lee HY et. al., 2012).This position has been reported to be a mutational hotspot (Mao CY et. al., 2014) and as such, this variant is considered one of the most common, recurrent causes of both PKD and benign familial infantile seizures (Steinlein OK et. al., 2012; Becker F et. al., 2013). The p.Arg217ProfsTer8 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This mutation creates a premature translational stop signal (p.Arg217Profs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.

Comment:

The frameshift variant c.649dupp.Arg217ProfsTer8 in PRRT2 gene has been reported previously in heterozygous state in individuals affected with benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia Wang Y, et al., 2017, Zheng W, et al., 2016. Experimental studies indicate that this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014. The variant is reported with 0.3% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic multiple submissions. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The observed frameshift c.649dup(p.Arg217ProfsTer8) variant in PRRT2 gene has been reported previously in heterozygous state in individual(s) affected with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (Steinlein et al., 2012; Chen GH., 2015). This variant is reported with the allele frequency of 0.4% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (Méneret et al., 2012). For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial infantile convulsions with paroxysmal choreoathetosis (MIM#602066), episodic kinesigenic dyskinesia 1 (MIM#128200), benign familial infantile seizures 2 (MIM#605751) and self-limited familial and non-familial infantile seizures (MONDO#0100024). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for paroxysmal kinesigenic dyskinesia (PMID: 29334453). (I) 0115 - Variants in this gene are known to have variable expressivity. Variation in phenotype has been reported within and between families with the same pathogenic variant (PMID: 29334453). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (514 heterozygotes, 0 homozygotes; variant did not pass quality filter). (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, PMIDs: 22101681, 26561923, 25502464). (SP) 0901 - This variant has strong evidence for segregation with disease (PMIDs: 22101681, 25502464). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This variant is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene. The variant has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members [PMID: 22101681, 22845787, 22243967, 23182655, 25522171, 26598493, 29334453]. It has also been reported to have reduced penetrance and variable expression between and within families. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID: 25457817].

Comment:

Our laboratory reported two molecular diagnoses in KCNQ2 (NM_172108.4, c.2332delC) and PRRT2 (NM_145239.2, c.649dup) in an individual with Ohtahara syndrome, severe developmental delay, seizure disorder, structural brain anomalies and eye anomalies, severe hypotonia, bilateral hearing loss, and dysmorphic features.

Comment:

The PRRT2 c.649dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Profs*8). This variant has previously been reported to be causative for a broad range of autosomal dominant PRRT2-related phenotypes such as paroxysmal kinesigenic dyskinesia, familial hemiplegic migraine, benign familial infantile epilepsy (BFIE), and paroxysmal torticollis (Chen et al. 2011. PubMed ID: 22101681; Li et al. 2013. PubMed ID: 23535490; Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493; Zhao et al. 2018. PubMed ID: 29285950). In addition to variable expressivity, reduced penetrance is also documented for this gene (Ebrahimi-Fakhari et al. 1993. PubMed ID: 29334453). The c.649dup is the most common pathogenic variant reported in the PRRT2 gene. Note that allele frequency estimates at this position in the gnomAD public population database may be inaccurate. In summary, we classify this variant as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PRRT2-Related Disorder.	Adam MP	-	2024	PMID: 29334453
Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network.	Denommé-Pichon AS	European journal of human genetics : EJHG	2022	PMID: 34782754
Exercise test for patients with new-onset paroxysmal kinesigenic dyskinesia.	Ji F	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2021	PMID: 33661484
Identification of a Premature Termination Mutation in the Proline-Rich Transmembrane Protein 2 Gene in a Chinese Family with Febrile Seizures.	Zheng W	Molecular neurobiology	2016	PMID: 25502464
The evolving spectrum of PRRT2-associated paroxysmal diseases.	Ebrahimi-Fakhari D	Brain : a journal of neurology	2015	PMID: 26598493
Characteristics of patients with benign partial epilepsy in infancy without PRRT2 mutations.	Sangu N	Epilepsy research	2015	PMID: 26561923
PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling.	Li M	International journal of molecular sciences	2015	PMID: 25915028
Five cases of paroxysmal kinesigenic dyskinesia by genetic diagnosis.	Chen GH	Experimental and therapeutic medicine	2015	PMID: 25667652
PRRT2 mutations are related to febrile seizures in epileptic patients.	He ZW	International journal of molecular sciences	2014	PMID: 25522171
PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia.	Wu L	Parkinsonism & related disorders	2014	PMID: 25457817
PRRT2 and hemiplegic migraine: a complex association.	Pelzer N	Neurology	2014	PMID: 24928127
Novel phenotype in a family with infantile convulsions and paroxysmal choreoathetosis syndrome and PRRT2 gene mutation.	Fusco C	Brain & development	2014	PMID: 24074546
Girl with a PRRT2 mutation and infantile focal epilepsy with bilateral spikes.	Torisu H	Brain & development	2014	PMID: 23768507
Phenotypes and PRRT2 mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis.	Yang X	BMC neurology	2013	PMID: 24370076
Clinical and polygraphic study of familial paroxysmal kinesigenic dyskinesia with PRRT2 mutation.	Fabbri M	Epileptic disorders : international epilepsy journal with videotape	2013	PMID: 23771590
PRRT2-related disorders: further PKD and ICCA cases and review of the literature.	Becker F	Journal of neurology	2013	PMID: 23299620
PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins.	Castiglioni C	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2013	PMID: 23182655
Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation.	Sheerin UM	Journal of neurology	2013	PMID: 23180180
Familial Paroxysmal Kinesigenic Dyskinesia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301633
Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences.	Labate A	Epilepsia	2012	PMID: 23126439
PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine.	Marini C	Neurology	2012	PMID: 23077026
PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.	Gardiner AR	Neurology	2012	PMID: 23077024
PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.	Cloarec R	Neurology	2012	PMID: 23077017
The PRRT2 mutation c.649dupC is the so far most frequent cause of benign familial infantile convulsions.	Steinlein OK	Seizure	2012	PMID: 22877996
PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions.	van Vliet R	Neurology	2012	PMID: 22875091
PRRT2 mutations in paroxysmal kinesigenic dyskinesia with infantile convulsions in a Taiwanese cohort.	Lee YC	PloS one	2012	PMID: 22870186
Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine.	Dale RC	Developmental medicine and child neurology	2012	PMID: 22845787
Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.	Lee HY	Cell reports	2012	PMID: 22832103
Two faces of the same coin: benign familial infantile seizures and paroxysmal kinesigenic dyskinesia caused by PRRT2 mutations.	Schmidt A	Archives of neurology	2012	PMID: 22782515
PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population.	Méneret A	Neurology	2012	PMID: 22744660
PRRT2 mutations are the major cause of benign familial infantile seizures.	Schubert J	Human mutation	2012	PMID: 22623405
Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions.	Ono S	Journal of human genetics	2012	PMID: 22399141
PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.	Heron SE	American journal of human genetics	2012	PMID: 22243967
Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.	Liu Q	Journal of medical genetics	2012	PMID: 22209761
Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis.	Li J	Journal of medical genetics	2012	PMID: 22131361
Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.	Wang JL	Brain : a journal of neurology	2011	PMID: 22120146
Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia.	Chen WJ	Nature genetics	2011	PMID: 22101681
Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome.	Caraballo R	American journal of human genetics	2001	PMID: 11179027
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Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_145239.3(PRRT2):c.649dup (p.Arg217fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...