NM_001943.5(DSG2):c.145C>A (p.Arg49Ser) AND Arrhythmogenic right ventricular cardiomyopathy, type 10

Clinical significance:Uncertain significance (Last evaluated: Jan 30, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000526721.1

Allele description [Variation Report for NM_001943.5(DSG2):c.145C>A (p.Arg49Ser)]

NM_001943.5(DSG2):c.145C>A (p.Arg49Ser)

Gene:
DSG2:desmoglein 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_001943.5(DSG2):c.145C>A (p.Arg49Ser)
HGVS:
  • NC_000018.10:g.31519866C>A
  • NG_007072.3:g.26625C>A
  • NM_001943.5:c.145C>AMANE SELECT
  • NP_001934.2:p.Arg49Ser
  • LRG_397t1:c.145C>A
  • LRG_397:g.26625C>A
  • NC_000018.9:g.29099829C>A
  • NM_001943.3:c.145C>A
Protein change:
R49S
Links:
dbSNP: rs762526848
NCBI 1000 Genomes Browser:
rs762526848
Molecular consequence:
  • NM_001943.5:c.145C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Arrhythmogenic right ventricular cardiomyopathy, type 10 (ARVD10)
Synonyms:
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; Arrhythmogenic right ventricular dysplasia type 10; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy10
Identifiers:
MONDO: MONDO:0012434; MedGen: C1857777; OMIM: 610193

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000641963Invitaecriteria provided, single submitter
Uncertain significance
(Jan 30, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000641963.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces arginine with serine at codon 49 of the DSG2 protein (p.Arg49Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg49His) has been determined to be pathogenic (PMID: 16773573, 19151369). This suggests that the arginine residue is critical for DSG2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change with deleterious impact on protein function. In the absence of segregation or functional evidence, It has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 25, 2021

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