VCV000044874.52 - ClinVar

NM_004415.4(DSP):c.2422C>T (p.Arg808Cys)

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.

(12)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004415.4(DSP):c.2422C>T (p.Arg808Cys)

Variation ID: 44874 Accession: VCV000044874.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p24.3 6: 7574781 (GRCh38) [ NCBI UCSC ] 6: 7575014 (GRCh37) [ NCBI UCSC ] 6: 7520013 (NCBI36) [ 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	Dec 6, 2014	Oct 20, 2024	Apr 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004415.4:c.2422C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004406.2:p.Arg808Cys	missense
NM_001008844.3:c.2422C>T	NP_001008844.1:p.Arg808Cys	missense
NM_001319034.2:c.2422C>T	NP_001305963.1:p.Arg808Cys	missense
NC_000006.12:g.7574781C>T
NC_000006.11:g.7575014C>T
NG_008803.1:g.38145C>T
LRG_423:g.38145C>T
LRG_423t1:c.2422C>T

... more HGVS ... less HGVS

Protein change

R808C

Other names

Canonical SPDI

NC_000006.12:7574780: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.

0.00020 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00017

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00021

The Genome Aggregation Database (gnomAD), exomes 0.00030

Exome Aggregation Consortium (ExAC) 0.00037

Links

ClinGen: CA004124 dbSNP: rs150339369 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.
DSP		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4762	4976

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	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Apr 9, 2024	RCV000038008.9
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (2)	criteria provided, single submitter	Apr 5, 2018	RCV000148478.6
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2017	RCV000641847.25
Lethal acantholytic epidermolysis bullosa	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2018	RCV001159872.5
Arrhythmogenic right ventricular dysplasia 8	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2018	RCV001159871.5
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Mar 28, 2022	RCV000622195.4
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Arrhythmogenic right ventricular dysplasia 8	Likely benign (1)	criteria provided, single submitter	Jan 19, 2024	RCV001084249.9
Woolly hair-skin fragility syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 19, 2018	RCV001159873.5
Cardiomyopathy	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 27, 2018	RCV000777603.7

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 (Nov 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061674.6 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 21756917‚ 23861362‚ 25569433‚ 25351510‚ 27153395 Comment: The p.Arg808Cys variant in DSP has been reported in 6 individuals: 1 with DCM, 2 with HCM, 1 with LVH, and 3 with ARVC (Lopes … (more) The p.Arg808Cys variant in DSP has been reported in 6 individuals: 1 with DCM, 2 with HCM, 1 with LVH, and 3 with ARVC (Lopes 2015, Ng 2013, Al-Jassar 2011, Marschall 2019 PMID: 31737537, http://arvcdatabase.info/, LMM unpublished data). However, this variant has also been identified in 0.3% (32/10368) of Ashkenazi Jewish chromosomes and 0.028% (37/129158) European chromosomes, including 1 homozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This variant is reported in ClinVar (Variation ID: 44874). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the frequency of this variant suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1. (less)
Likely benign (Jun 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000913470.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Arrhythmogenic right ventricular dysplasia 8 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000763497.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024
Likely benign (Mar 28, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735485.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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 (Apr 09, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076865.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (2) PubMed: 23396983‚ 25163546 Comment: Variant summary: DSP c.2422C>T (p.Arg808Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: DSP c.2422C>T (p.Arg808Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251444 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is benign. c.2422C>T has been reported in the literature in individuals affected with Cardiomyopathy without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25163546, 23396983). ClinVar contains an entry for this variant (Variation ID: 44874). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Uncertain significance (Apr 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cardiomyopathy, arrhythmogenic right ventricular Affected status: no Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Accession: SCV000055163.3 First in ClinVar: Jun 08, 2015 Last updated: Sep 14, 2015 Comments (2): The study set was not selected for affection status in relation to arrhythmia or cardiomyopathy. Pathogenicity categories were based on literature curation. See Pubmed ID:25741868 … (more) The study set was not selected for affection status in relation to arrhythmia or cardiomyopathy. Pathogenicity categories were based on literature curation. See Pubmed ID:25741868 for details. (less) Medical sequencing	Number of individuals with the variant: 1 Secondary finding: yes
Uncertain significance (Jan 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 8 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001321617.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (7) PubMed: 25569433‚ 23861362‚ 23299917‚ 26332594‚ 21756917‚ 25637381‚ 27153395 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Jan 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lethal acantholytic epidermolysis bullosa Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001321618.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (7) PubMed: 26332594‚ 23299917‚ 23861362‚ 25637381‚ 25569433‚ 21756917‚ 27153395 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Jan 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001321619.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (7) PubMed: 25637381‚ 21756917‚ 26332594‚ 27153395‚ 23861362‚ 25569433‚ 23299917 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Jan 01, 2017)	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: SCV001154633.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Dec 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333762.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Cardiomyopathy, arrhythmogenic right ventricular (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190180.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Comment:

The p.Arg808Cys variant in DSP has been reported in 6 individuals: 1 with DCM, 2 with HCM, 1 with LVH, and 3 with ARVC (Lopes 2015, Ng 2013, Al-Jassar 2011, Marschall 2019 PMID: 31737537, http://arvcdatabase.info/, LMM unpublished data). However, this variant has also been identified in 0.3% (32/10368) of Ashkenazi Jewish chromosomes and 0.028% (37/129158) European chromosomes, including 1 homozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This variant is reported in ClinVar (Variation ID: 44874). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the frequency of this variant suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1.

Comment:

This alteration is classified as likely 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.

Comment:

Variant summary: DSP c.2422C>T (p.Arg808Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251444 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is benign. c.2422C>T has been reported in the literature in individuals affected with Cardiomyopathy without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25163546, 23396983). ClinVar contains an entry for this variant (Variation ID: 44874). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

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
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.	Jurgens J	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25569433
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Atlas of the clinical genetics of human dilated cardiomyopathy.	Haas J	European heart journal	2015	PMID: 25163546
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations.	Al-Jassar C	Journal of molecular biology	2011	PMID: 21756917

Text-mined citations for rs150339369 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004415.4(DSP):c.2422C>T (p.Arg808Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150339369 ...