VCV000072377.17 - ClinVar

NM_024422.6(DSC2):c.607C>T (p.Arg203Cys)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024422.6(DSC2):c.607C>T (p.Arg203Cys)

Variation ID: 72377 Accession: VCV000072377.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31089462 (GRCh38) [ NCBI UCSC ] 18: 28669425 (GRCh37) [ NCBI UCSC ] 18: 26923423 (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	May 29, 2016	May 1, 2024	Oct 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024422.6:c.607C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077740.1:p.Arg203Cys	missense
NM_004949.5:c.607C>T	NP_004940.1:p.Arg203Cys	missense
NC_000018.10:g.31089462G>A
NC_000018.9:g.28669425G>A
NG_008208.2:g.17964C>T
LRG_400:g.17964C>T
	Q02487:p.Arg203Cys

... more HGVS ... less HGVS

Protein change

R203C

Other names

Canonical SPDI

NC_000018.10:31089461: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA022869 UniProtKB: Q02487#VAR_065687 dbSNP: rs142331975 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	1575	1711

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	Uncertain significance (1)	criteria provided, single submitter	Sep 22, 2015	RCV000155026.5
Arrhythmogenic right ventricular dysplasia 11	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 15, 2023	RCV001065143.13
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2022	RCV004019075.1

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 (Sep 22, 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: SCV000204709.4 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016	Publications: PubMed (3) PubMed: 21062920‚ 18957847‚ 23514727 Comment: Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg203Cys variant in DSC2 has been reported in 1 heterozygous Caucasian individual with A RVC (Gehmlich … (more) Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg203Cys variant in DSC2 has been reported in 1 heterozygous Caucasian individual with A RVC (Gehmlich 2011) and in 1 Japanese individual with ARVC who carried 2 additio nal DSC2 variants (Ohno 2013). Testing of relatives of the proband reported by O hno 2013 detected the Arg203Cys variant in 1 of 2 relatives with a possible diag nosis of ARVC. This variant has been previously identified by our laboratory in two homozygous adults of Middle Eastern descent with ARVC and biventricular DCM, one of whom had additional minimal features of recessive ARVC. The variant was absent from large population studies but it should be noted that these did not s urvey a large enough number of Middle Eastern individuals to rule out that it is common in this population. Cell culture studies do suggest that the variant aff ects protein function (Gehmlich 2011) although these types of studies may not ac curately reflect biological function. Computational predictions also support tha t the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg203Cys variant is unce rtain. (less) Number of individuals with the variant: 4
Uncertain significance (Nov 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984559.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Uncertain significance (Sep 08, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004858872.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.607C>T (p.R203C) alteration is located in exon 5 (coding exon 5) of the DSC2 gene. This alteration results from a C to T substitution … (more) The c.607C>T (p.R203C) alteration is located in exon 5 (coding exon 5) of the DSC2 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 11 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367679.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more) This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. (less)
Uncertain significance (Oct 15, 2023)	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: SCV001230086.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 21062920‚ 23514727‚ 25825460‚ 21636032 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the DSC2 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the DSC2 protein (p.Arg203Cys). This variant is present in population databases (rs142331975, gnomAD 0.0009%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21062920, 23514727, 25825460). ClinVar contains an entry for this variant (Variation ID: 72377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DSC2 protein function. Experimental studies have shown that this missense change affects DSC2 function (PMID: 21062920). This variant disrupts the p.Arg203 amino acid residue in DSC2. Other variant(s) that disrupt this residue have been observed in individuals with DSC2-related conditions (PMID: 21636032), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg203Cys variant in DSC2 has been reported in 1 heterozygous Caucasian individual with A RVC (Gehmlich 2011) and in 1 Japanese individual with ARVC who carried 2 additio nal DSC2 variants (Ohno 2013). Testing of relatives of the proband reported by O hno 2013 detected the Arg203Cys variant in 1 of 2 relatives with a possible diag nosis of ARVC. This variant has been previously identified by our laboratory in two homozygous adults of Middle Eastern descent with ARVC and biventricular DCM, one of whom had additional minimal features of recessive ARVC. The variant was absent from large population studies but it should be noted that these did not s urvey a large enough number of Middle Eastern individuals to rule out that it is common in this population. Cell culture studies do suggest that the variant aff ects protein function (Gehmlich 2011) although these types of studies may not ac curately reflect biological function. Computational predictions also support tha t the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg203Cys variant is unce rtain.

Comment:

The c.607C>T (p.R203C) alteration is located in exon 5 (coding exon 5) of the DSC2 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the DSC2 protein (p.Arg203Cys). This variant is present in population databases (rs142331975, gnomAD 0.0009%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21062920, 23514727, 25825460). ClinVar contains an entry for this variant (Variation ID: 72377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DSC2 protein function. Experimental studies have shown that this missense change affects DSC2 function (PMID: 21062920). This variant disrupts the p.Arg203 amino acid residue in DSC2. Other variant(s) that disrupt this residue have been observed in individuals with DSC2-related conditions (PMID: 21636032), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.	Protonotarios A	Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology	2016	PMID: 25825460
Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.	Ohno S	Circulation journal : official journal of the Japanese Circulation Society	2013	PMID: 23514727
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.	Kapplinger JD	Journal of the American College of Cardiology	2011	PMID: 21636032
Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations.	Gehmlich K	Cardiovascular research	2011	PMID: 21062920
Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair.	Simpson MA	Cardiology	2009	PMID: 18957847

Text-mined citations for rs142331975 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_024422.6(DSC2):c.607C>T (p.Arg203Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142331975 ...