VCV000180318.28 - ClinVar

NM_024422.6(DSC2):c.2497C>T (p.Arg833Cys)

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.

(8)

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(1); Benign(2); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024422.6(DSC2):c.2497C>T (p.Arg833Cys)

Variation ID: 180318 Accession: VCV000180318.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31068905 (GRCh38) [ NCBI UCSC ] 18: 28648871 (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	Feb 7, 2015	May 1, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024422.6:c.2497C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077740.1:p.Arg833Cys	missense
NM_004949.5:c.2497C>T	NP_004940.1:p.Arg833Cys	missense
NC_000018.10:g.31068905G>A
NC_000018.9:g.28648871G>A
NG_008208.2:g.38521C>T
LRG_400:g.38521C>T

... more HGVS ... less HGVS

Protein change

R833C

Other names

p.R833C:CGT>TGT

Canonical SPDI

NC_000018.10:31068904: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.

0.00200 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00023

The Genome Aggregation Database (gnomAD) 0.00045

1000 Genomes Project 30x 0.00187

1000 Genomes Project 0.00200

Links

ClinGen: CA022747 dbSNP: rs142410803 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.
DSC2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1578	1715

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.
Arrhythmogenic right ventricular dysplasia 11	Benign (1)	criteria provided, single submitter	Jan 25, 2024	RCV000461186.19
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Mar 17, 2014	RCV000157175.9
Cardiomyopathy	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 19, 2018	RCV000770529.13
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Aug 29, 2016	RCV000181166.14
Hypertrophic cardiomyopathy	Likely benign (1)	criteria provided, single submitter	May 8, 2018	RCV000852735.8
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jan 23, 2018	RCV002426764.9

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.
Uncertain significance (Oct 23, 2015)	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 Study: Canadian Open Genetics Repository Accession: SCV000901976.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Likely benign (Apr 23, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000270162.2 First in ClinVar: May 29, 2016 Last updated: Oct 09, 2016	Publications: PubMed (1) PubMed: 21636032 Comment: p.Arg833Cys in exon 15 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (43/8636) of … (more) p.Arg833Cys in exon 15 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (43/8636) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142410803). Arginine (Arg) at position 833 is not conserved in mammals or evolutionarily distant species and 1 mammal (cape elephant shrew) carries a c ysteine (Cys) at this position, further supporting that this change may be toler ated. (less) Number of individuals with the variant: 1
Benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000561712.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Benign (Aug 29, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233443.12 First in ClinVar: Jul 05, 2015 Last updated: Oct 09, 2016	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)
Likely benign (Apr 19, 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: SCV000913482.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Jan 23, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002741857.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 21636032 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 (May 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995450.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Uncertain significance (Mar 17, 2014)	no assertion criteria provided Method: clinical testing	Arrhythmogenic right ventricular cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000206899.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015 Comment: Found together with likely pathogenic DSC2:NM_024422.3:c.2368_2370delGGA	Publications: PubMed (1) PubMed: 21636032 Number of individuals with the variant: 1

Comment:

p.Arg833Cys in exon 15 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (43/8636) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142410803). Arginine (Arg) at position 833 is not conserved in mammals or evolutionarily distant species and 1 mammal (cape elephant shrew) carries a c ysteine (Cys) at this position, further supporting that this change may be toler ated.

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 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.

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
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.	Kapplinger JD	Journal of the American College of Cardiology	2011	PMID: 21636032

Text-mined citations for rs142410803 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_024422.6(DSC2):c.2497C>T (p.Arg833Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142410803 ...