VCV000002643.81 - ClinVar

NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)

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.

(30)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)

Variation ID: 2643 Accession: VCV000002643.81

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6617040 (GRCh38) [ NCBI UCSC ] 11: 6638271 (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	Oct 1, 2013	Oct 20, 2024	Mar 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000391.4:c.622C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000382.3:p.Arg208Ter	nonsense
NC_000011.10:g.6617040G>A
NC_000011.9:g.6638271G>A
NG_008653.1:g.7422C>T
LRG_830:g.7422C>T
LRG_830t1:c.622C>T	LRG_830p1:p.Arg208Ter

... more HGVS ... less HGVS

Protein change

R208*

Other names

p.R208*:CGA>TGA

Canonical SPDI

NC_000011.10:6617039:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00017

The Genome Aggregation Database (gnomAD), exomes 0.00022

Trans-Omics for Precision Medicine (TOPMed) 0.00023

The Genome Aggregation Database (gnomAD) 0.00025

Links

ClinGen: CA319182 Genetic Testing Registry (GTR): GTR000330881 OMIM: 607998.0003 dbSNP: rs119455955 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.
TPP1		-	-	GRCh38 GRCh37	1154	1185

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.
Neuronal ceroid lipofuscinosis 2	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Jan 18, 2022	RCV000002762.31
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 26, 2021	RCV000210605.6
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000189769.40
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001813939.3
Neuronal ceroid lipofuscinosis	Pathogenic (2)	criteria provided, single submitter	Aug 11, 2016	RCV000230952.11
TPP1-related disorder	Pathogenic (2)	criteria provided, single submitter	Mar 11, 2024	RCV004554580.3
Autosomal recessive spinocerebellar ataxia 7 Neuronal ceroid lipofuscinosis 2	Pathogenic (2)	criteria provided, single submitter	Jan 31, 2022	RCV000763267.5

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 (Mar 22, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ceroid lipofuscinosis, neuronal, 2 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000597531.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Pathogenic (Nov 07, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744909.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163320.1 First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194158.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020	Publications: PubMed (5) PubMed: 15317752‚ 9788728‚ 21990111‚ 23539563‚ 10330339 Comment: NM_000391.3(TPP1):c.622C>T(R208) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited … (more) NM_000391.3(TPP1):c.622C>T(R208) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited for classification include the following: PMID 15317752, 9788728, 21990111, 23539563 and 10330339. Classification of NM_000391.3(TPP1):c.622C>T(R208*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ (less)
Pathogenic (Sep 25, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001426166.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020
Pathogenic (Jan 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366393.2 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,PS1,PM2.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: biparental	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004042679.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1
Pathogenic (Nov 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022403.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284808.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 28492532‚ 10330339‚ 9295267‚ 23539563‚ 26026925‚ 26795593 Comment: This sequence change creates a premature translational stop signal (p.Arg208) in the TPP1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg208) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs119455955, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9295267, 10330339, 23539563, 26026925, 26795593). ClinVar contains an entry for this variant (Variation ID: 2643). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 16, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615830.1 First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016	Publications: PubMed (28) PubMed: 17959406‚ 12796825‚ 12376936‚ 19793312‚ 22245569‚ 16814585‚ 16782851‚ 27553520‚ 26075876‚ 18473686‚ 10330339‚ 9788728‚ 11071145‚ 12488460‚ 11017954‚ 9295267‚ 12950156‚ 26795593‚ 23539563‚ 15317752‚ 19201763‚ 18684116‚ 18283468‚ 12414822‚ 27407112‚ 23418007‚ 23266810‚ 17679671
Pathogenic (Aug 11, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696667.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (3) PubMed: 10330339‚ 15317752‚ 18283468 Comment: Variant summary: The TPP1 c.622C>T (p.Arg208X) variant results in a premature termination codon, predicted to cause a truncated or absent TPP1 protein due to nonsense … (more) Variant summary: The TPP1 c.622C>T (p.Arg208X) variant results in a premature termination codon, predicted to cause a truncated or absent TPP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/121276 control chromosomes at a frequency of 0.0001732, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state and is reported as one of the most common pathogenic variants in the gene. In vitro functional studies reveal no translational product could be detected for the R208X mutant and enzyme activity was shown to be <10% and not significantly different from negative controls (Steinfeld_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a common disease causing variant and has been classified as pathogenic. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Autosomal recessive spinocerebellar ataxia 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893910.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 14, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915543.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (6) PubMed: 12950156‚ 15317752‚ 28464005‚ 9295267‚ 26795593‚ 10330339 Comment: The TPP1 c.622C>T (p.Arg208Ter) variant is a stop-gained variant predicted to result in in a premature termination of the protein. The p.Arg206Ter variant has been … (more) The TPP1 c.622C>T (p.Arg208Ter) variant is a stop-gained variant predicted to result in in a premature termination of the protein. The p.Arg206Ter variant has been reported in at least five studies in which it was identified in 31 affected individuals, including in six in a homozygous state and in 25 in a compound heterozygous state, two of whom are siblings (Sleat et al. 1997; Sleat et al. 1999; BarisiÄ‡ et al. 2003; Helbig et al. 2016). Thirty of the individuals were diagnosed with neuronal ceroid-lipofuscinoses with one compound heterozygote presenting with a diagnosis of focal epilepsy (Helbig et al. 2016). In one study, the p.Arg208Ter variant accounted for 28% of disease alleles. The variant was absent from four controls but is reported at a frequency of 0.000619 in the Other population of the Genome Aggregation Database. Functional studies in HEK and CHO cells transfected with the variant showed that the variant resulted in enzymatic activity of 3.3% and 2.8% respectively compared to 100% in wild type (Steinfeld et al. 2004). A mouse model created by Geraets et al. (2017) mimicked the human disease very closely. TPP1 activity was found to be reduced by at least 90% compared to the wild type mice with Cln2 transcript levels reduced by 60-90% in tissue samples from a range of organs. Based on the collective evidence, the p.Arg208Ter variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755651.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Apr 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000243417.12 First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019	Comment: Published functional studies demonstrate damaging effects, including a reduction in transcript abundance and enzyme activity (Geraets et al., 2017); Nonsense variant predicted to result in … (more) Published functional studies demonstrate damaging effects, including a reduction in transcript abundance and enzyme activity (Geraets et al., 2017); Nonsense 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; This variant is associated with the following publications: (PMID: 19793312, 23539563, 12363103, 9788728, 21940688, 11071145, 12414822, 12796825, 18283468, 26795593, 29631617, 29554876, 15317752, 25525159, 20301601, 10665500, 18684116, 21990111, 9295267, 10330339, 12950156, 28464005, 29655203, 30541466, 30945278, 31170314, 31122803, 31980526, 32412666, 33845243, 31589614) (less)
Pathogenic (Jan 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580602.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4, PM2_SUP	Number of individuals with the variant: 2 Sex: male
Pathogenic (Jan 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Autosomal recessive spinocerebellar ataxia 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611330.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 31, 2022
Pathogenic (Mar 24, 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: SCV004227217.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (8) PubMed: 12796825‚ 12950156‚ 15317752‚ 25525159‚ 29631617‚ 29687370‚ 31122803‚ 32412666 Comment: PM2, PS3, PS4_moderate, PVS1 Number of individuals with the variant: 1
Pathogenic (Feb 26, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000262903.6 First in ClinVar: Apr 09, 2016 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 9295267‚ 12950156‚ 23539563‚ 26795593 Comment: The c.622C>T (p.R208) alteration, located in exon 6 (coding exon 6) of the TPP1 gene, consists of a C to T substitution at nucleotide position … (more) The c.622C>T (p.R208) alteration, located in exon 6 (coding exon 6) of the TPP1 gene, consists of a C to T substitution at nucleotide position 622. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 208. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation is one of the most common TPP1 mutations and has been detected in both the homozygous and compound heterozygous states in various individuals with neuronal ceroid lipofuscinosis (Sleat, 1997; Barisi, 2003; Miller, 2013; Helbig, 2016). This mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller, 2013). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TPP1-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005043909.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Comment: PVS1, PM3_Strong
Pathogenic (Feb 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: SCV001748276.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Comment: TPP1: PM3:Very Strong, PVS1, PM2, PS3:Supporting Number of individuals with the variant: 6
Pathogenic (Sep 19, 1997)	no assertion criteria provided Method: literature only	CEROID LIPOFUSCINOSIS, NEURONAL, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022920.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2015	Publications: PubMed (1) PubMed: 9295267 Comment on evidence: In 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) found compound heterozygosity for a C-to-T transition that resulted … (more) In 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) found compound heterozygosity for a C-to-T transition that resulted in the conversion of codon 208 (CGA) to a stop codon (TGA). In the other allele, the conserved AG of the intronic 3-prime splice junction sequence was changed to AC, which was predicted to result in intron splicing (607998.0004). Each parent possessed a single different mutant allele. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001459947.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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) Study: VKGL Data-share Consensus Accession: SCV001798173.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	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: SCV001959365.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101088.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	TPP1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004121302.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The TPP1 c.622C>T variant is predicted to result in premature protein termination (p.Arg208). This is one of the most commonly reported TPP1 variants in individuals … (more) The TPP1 c.622C>T variant is predicted to result in premature protein termination (p.Arg208). This is one of the most commonly reported TPP1 variants in individuals with neuronal ceroid lipofuscinosis; it has been observed in the homozygous state or with a second TPP1 variant in affected individuals (for example, see Sleat et al. 1997. PubMed ID: 9295267; Barisić et al. 2003. PubMed ID: 12950156; Miller et al. 2013. PubMed ID: 23539563; Geraets et al. 2017. PubMed ID: 28464005). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in TPP1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733089.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Aug 17, 2012)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000804935.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
not provided (-)	no classification provided Method: literature only	Neuronal ceroid lipofuscinosis 2 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086785.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 10330339‚ 9788728‚ 20301601 BookShelf: NBK1428 BookShelf: NBK1428
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Comment:

NM_000391.3(TPP1):c.622C>T(R208*) is classified as pathogenic in the context of TPP1-related neuronal ceroid lipofuscinosis and is associated with the late-infantile form of this disease. Sources cited for classification include the following: PMID 15317752, 9788728, 21990111, 23539563 and 10330339. Classification of NM_000391.3(TPP1):c.622C>T(R208*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£

Comment:

This sequence change creates a premature translational stop signal (p.Arg208*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs119455955, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9295267, 10330339, 23539563, 26026925, 26795593). ClinVar contains an entry for this variant (Variation ID: 2643). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: The TPP1 c.622C>T (p.Arg208X) variant results in a premature termination codon, predicted to cause a truncated or absent TPP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/121276 control chromosomes at a frequency of 0.0001732, which does not exceed the estimated maximal expected allele frequency of a pathogenic TPP1 variant (0.002958). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state and is reported as one of the most common pathogenic variants in the gene. In vitro functional studies reveal no translational product could be detected for the R208X mutant and enzyme activity was shown to be <10% and not significantly different from negative controls (Steinfeld_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a common disease causing variant and has been classified as pathogenic.

Comment:

The TPP1 c.622C>T (p.Arg208Ter) variant is a stop-gained variant predicted to result in in a premature termination of the protein. The p.Arg206Ter variant has been reported in at least five studies in which it was identified in 31 affected individuals, including in six in a homozygous state and in 25 in a compound heterozygous state, two of whom are siblings (Sleat et al. 1997; Sleat et al. 1999; BarisiÄ‡ et al. 2003; Helbig et al. 2016). Thirty of the individuals were diagnosed with neuronal ceroid-lipofuscinoses with one compound heterozygote presenting with a diagnosis of focal epilepsy (Helbig et al. 2016). In one study, the p.Arg208Ter variant accounted for 28% of disease alleles. The variant was absent from four controls but is reported at a frequency of 0.000619 in the Other population of the Genome Aggregation Database. Functional studies in HEK and CHO cells transfected with the variant showed that the variant resulted in enzymatic activity of 3.3% and 2.8% respectively compared to 100% in wild type (Steinfeld et al. 2004). A mouse model created by Geraets et al. (2017) mimicked the human disease very closely. TPP1 activity was found to be reduced by at least 90% compared to the wild type mice with Cln2 transcript levels reduced by 60-90% in tissue samples from a range of organs. Based on the collective evidence, the p.Arg208Ter variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Published functional studies demonstrate damaging effects, including a reduction in transcript abundance and enzyme activity (Geraets et al., 2017); Nonsense 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; This variant is associated with the following publications: (PMID: 19793312, 23539563, 12363103, 9788728, 21940688, 11071145, 12414822, 12796825, 18283468, 26795593, 29631617, 29554876, 15317752, 25525159, 20301601, 10665500, 18684116, 21990111, 9295267, 10330339, 12950156, 28464005, 29655203, 30541466, 30945278, 31170314, 31122803, 31980526, 32412666, 33845243, 31589614)

Comment:

The c.622C>T (p.R208*) alteration, located in exon 6 (coding exon 6) of the TPP1 gene, consists of a C to T substitution at nucleotide position 622. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 208. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation is one of the most common TPP1 mutations and has been detected in both the homozygous and compound heterozygous states in various individuals with neuronal ceroid lipofuscinosis (Sleat, 1997; Barisi, 2003; Miller, 2013; Helbig, 2016). This mutation has been shown to significantly impact both TPP1 fold regulation and enzyme activity (Miller, 2013). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The TPP1 c.622C>T variant is predicted to result in premature protein termination (p.Arg208*). This is one of the most commonly reported TPP1 variants in individuals with neuronal ceroid lipofuscinosis; it has been observed in the homozygous state or with a second TPP1 variant in affected individuals (for example, see Sleat et al. 1997. PubMed ID: 9295267; Barisić et al. 2003. PubMed ID: 12950156; Miller et al. 2013. PubMed ID: 23539563; Geraets et al. 2017. PubMed ID: 28464005). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in TPP1 are expected to be pathogenic. This variant is interpreted 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
Neuronal ceroid lipofuscinosis in the Russian population: Two novel mutations and the prevalence of heterozygous carriers.	Kozina AA	Molecular genetics & genomic medicine	2020	PMID: 32412666
Perampanel attenuates myoclonus in a patient with neuronal ceroid lipofuscinoses type 2 disease.	Wong LC	Brain & development	2019	PMID: 31122803
Performance comparison of two whole genome amplification techniques in frame of multifactor preimplantation genetic testing.	Volozonoka L	Journal of assisted reproduction and genetics	2018	PMID: 29687370
Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.	Sima N	Orphanet journal of rare diseases	2018	PMID: 29631617
A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies.	Geraets RD	PloS one	2017	PMID: 28464005
Analysis of large-scale whole exome sequencing data to determine the prevalence of genetically-distinct forms of neuronal ceroid lipofuscinosis.	Sleat DE	Gene	2016	PMID: 27553520
Novel small molecules potentiate premature termination codon readthrough by aminoglycosides.	Baradaran-Heravi A	Nucleic acids research	2016	PMID: 27407112
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.	Helbig KL	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26795593
Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway.	Di Fruscio G	Autophagy	2015	PMID: 26075876
Genetics of the neuronal ceroid lipofuscinoses (Batten disease).	Mole SE	Biochimica et biophysica acta	2015	PMID: 26026925
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis.	Miller JN	Human molecular genetics	2013	PMID: 23539563
Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).	Sun Y	Human mutation	2013	PMID: 23418007
Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America.	Kohan R	Gene	2013	PMID: 23266810
Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301601
Clinical study in Chinese patients with late-infantile form neuronal ceroid lipofuscinoses.	Chang X	Brain & development	2012	PMID: 22245569
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.	Kousi M	Human mutation	2012	PMID: 21990111
An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients.	Kohan R	Clinical genetics	2009	PMID: 19793312
Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis.	Kousi M	Brain : a journal of neurology	2009	PMID: 19201763
The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.	Moore SJ	Clinical genetics	2008	PMID: 18684116
Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.	Worgall S	Human gene therapy	2008	PMID: 18473686
Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency.	Elleder M	Acta neuropathologica	2008	PMID: 18283468
CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype.	Bessa C	Molecular genetics and metabolism	2008	PMID: 17959406
Neurological deterioration in late infantile neuronal ceroid lipofuscinosis.	Worgall S	Neurology	2007	PMID: 17679671
Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights into molecular mechanisms of CLN5 deficiency.	Bessa C	Molecular genetics and metabolism	2006	PMID: 16814585
Detection of tripeptidyl peptidase I activity in living cells by fluorogenic substrates.	Steinfeld R	The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society	2006	PMID: 16782851
Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes.	Steinfeld R	Human molecular genetics	2004	PMID: 15317752
R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis.	Barisić N	Croatian medical journal	2003	PMID: 12950156
Clinicopathological and molecular characterization of neuronal ceroid lipofuscinosis in the Portuguese population.	Teixeira C	Journal of neurology	2003	PMID: 12796825
Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.	Golabek AA	The Journal of biological chemistry	2003	PMID: 12488460
Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles.	Ju W	Journal of medical genetics	2002	PMID: 12414822
Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.	Steinfeld R	American journal of medical genetics	2002	PMID: 12376936
A CLN2 gene nonsense mutation is associated with severe caudate atrophy and dystonia in LINCL.	Simonati A	Neuropediatrics	2000	PMID: 11071145
Rapid detection of the two most common CLN2 mutations causing classical late infantile neuronal ceroid lipofuscinosis.	Bodzioch M	Clinical chemistry	2000	PMID: 11017954
Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.	Sleat DE	American journal of human genetics	1999	PMID: 10330339
Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipofuscinosis.	Zhong N	Clinical genetics	1998	PMID: 9788728
Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.	Sleat DE	Science (New York, N.Y.)	1997	PMID: 9295267
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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs119455955 ...