VCV000096494.90 - ClinVar

NM_145239.3(PRRT2):c.647C>T (p.Pro216Leu)

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.

(15)

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.

Benign/Likely benign

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.647C>T (p.Pro216Leu)

Variation ID: 96494 Accession: VCV000096494.90

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p11.2 16: 29813701 (GRCh38) [ NCBI UCSC ] 16: 29825022 (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	Jun 8, 2016	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_145239.3:c.647C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_660282.2:p.Pro216Leu	missense
NM_001256442.2:c.647C>T	NP_001243371.1:p.Pro216Leu	missense
NM_001256443.2:c.647C>T	NP_001243372.1:p.Pro216Leu	missense
NC_000016.10:g.29813701C>T
NC_000016.9:g.29825022C>T
NG_032039.1:g.6614C>T
	Q7Z6L0:p.Pro216Leu

... more HGVS ... less HGVS

Protein change

P216L

Other names

p.P216L:CCC>CTC

Canonical SPDI

NC_000016.10:29813700:C:T

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.

0.00240 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00528

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00568

1000 Genomes Project 0.00240

1000 Genomes Project 30x 0.00265

Links

ClinGen: CA285795 UniProtKB: Q7Z6L0#VAR_067321 dbSNP: rs76335820 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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Dec 30, 2019	RCV000082646.25
Episodic kinesigenic dyskinesia	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001082873.18
not provided	Likely benign (7)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000224146.39
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Jul 7, 2016	RCV002311740.9
Seizure	Uncertain significance (1)	no assertion criteria provided	-	RCV002274919.8
Episodic kinesigenic dyskinesia 1 Infantile convulsions and choreoathetosis Seizures, benign familial infantile, 2	Likely benign (1)	criteria provided, single submitter	Aug 13, 2021	RCV002505010.8

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.
Likely Benign (Apr 21, 2016)	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: SCV000280979.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (Aug 27, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000152395.3 First in ClinVar: May 17, 2014 Last updated: Nov 10, 2017
Benign (Dec 11, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171201.12 First in ClinVar: Jun 23, 2014 Last updated: Nov 10, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Dec 30, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475995.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (7) PubMed: 24828792‚ 23077024‚ 23566103‚ 24594579‚ 31124310‚ 23529024‚ 22243967
Likely benign (Aug 13, 2021)	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: SCV002810577.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Feb 01, 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: SCV000291480.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Jul 07, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000845845.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005215749.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (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: SCV001150889.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: PRRT2: PM5, BS1, BS2 Number of individuals with the variant: 35
Benign (May 09, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114688.8 First in ClinVar: Jan 17, 2014 Last updated: Nov 10, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PRRT2 Number of individuals with the variant: 2 Sex: mixed
Likely benign (-)	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) Study: VKGL Data-share Consensus Accession: SCV001799297.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740471.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	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: SCV001930543.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Seizure Affected status: yes Allele origin: maternal	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV002562840.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956807.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders.	Zhao SY	CNS neuroscience & therapeutics	2020	PMID: 31124310
Towards the identification of a genetic basis for Landau-Kleffner syndrome.	Conroy J	Epilepsia	2014	PMID: 24828792
Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders.	Huguet G	PloS one	2014	PMID: 24594579
Mutations in PRRT2 are not a common cause of infantile epileptic encephalopathies.	Heron SE	Epilepsia	2013	PMID: 23566103
A novel mutation and functional implications of 5 variants in the PRRT2 gene in 20 paroxysmal kinesigenic dyskinesia pedigrees.	Jing XY	Parkinsonism & related disorders	2013	PMID: 23529024
PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.	Gardiner AR	Neurology	2012	PMID: 23077024
PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.	Heron SE	American journal of human genetics	2012	PMID: 22243967
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PRRT2	-	-	-	-

Text-mined citations for rs76335820 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_145239.3(PRRT2):c.647C>T (p.Pro216Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs76335820 ...