NM_024422.6(DSC2):c.607C>T (p.Arg203Cys) AND Arrhythmogenic right ventricular dysplasia 11

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001065143.13

Allele description [Variation Report for NM_024422.6(DSC2):c.607C>T (p.Arg203Cys)]

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

Gene:

DSC2:desmocollin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

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

HGVS:

NC_000018.10:g.31089462G>A
NG_008208.2:g.17964C>T
NM_004949.5:c.607C>T
NM_024422.6:c.607C>TMANE SELECT
NP_004940.1:p.Arg203Cys
NP_077740.1:p.Arg203Cys
LRG_400:g.17964C>T
NC_000018.8:g.26923423G>A
NC_000018.9:g.28669425G>A
NM_024422.3:c.607C>T
NM_024422.4:c.607C>T
Q02487:p.Arg203Cys

Protein change:

R203C

Links:

UniProtKB: Q02487#VAR_065687; dbSNP: rs142331975

NCBI 1000 Genomes Browser:

rs142331975

Molecular consequence:

NM_004949.5:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024422.6:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 11
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11; Arrhythmogenic right ventricular cardiomyopathy, type 11; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11
Identifiers:: MONDO: MONDO:0012506; MedGen: C1864850; OMIM: 610476

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Homo sapiens MLX interacting protein like (MLXIPL), transcript variant 4, mRNA
Homo sapiens MLX interacting protein like (MLXIPL), transcript variant 4, mRNA
gi|1676317155|ref|NM_032954.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001230086	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23514727, 25825460, 21062920, 21636032, 28492532
SCV001367679	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 17, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001984559	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001230086

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 15, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001367679

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 17, 2020)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001984559

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Ohno S, Nagaoka I, Fukuyama M, Kimura H, Itoh H, Makiyama T, Shimizu A, Horie M.

Circ J. 2013;77(6):1534-42. Epub 2013 Mar 20. Erratum in: Circ J. 2020;84(11):2123. doi: 10.1253/circj.CJ-66-0185.

PubMed [citation]

PMID:: 23514727

Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.

Protonotarios A, Anastasakis A, Panagiotakos DB, Antoniades L, Syrris P, Vouliotis A, Stefanadis C, Tsatsopoulou A, McKenna WJ, Protonotarios N.

Europace. 2016 Apr;18(4):610-6. doi: 10.1093/europace/euv061. Epub 2015 Mar 29.

PubMed [citation]

PMID:: 25825460
PMCID:: PMC5841562

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001230086.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367679.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital, SCV001984559.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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