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NM_001943.5(DSG2):c.991G>A (p.Glu331Lys) AND Arrhythmogenic right ventricular dysplasia 10

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 3, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000018309.34

Allele description [Variation Report for NM_001943.5(DSG2):c.991G>A (p.Glu331Lys)]

NM_001943.5(DSG2):c.991G>A (p.Glu331Lys)

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.991G>A (p.Glu331Lys)
HGVS:
  • NC_000018.10:g.31524865G>A
  • NG_007072.3:g.31624G>A
  • NM_001943.5:c.991G>AMANE SELECT
  • NP_001934.2:p.Glu331Lys
  • LRG_397t1:c.991G>A
  • LRG_397:g.31624G>A
  • LRG_397p1:p.Glu331Lys
  • NC_000018.9:g.29104828G>A
  • NM_001943.3:c.991G>A
  • NM_001943.4:c.991G>A
Protein change:
E331K; GLU331LYS
Links:
OMIM: 125671.0007; dbSNP: rs121913012
NCBI 1000 Genomes Browser:
rs121913012
Molecular consequence:
  • NM_001943.5:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Arrhythmogenic right ventricular dysplasia 10
Synonyms:
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; Arrhythmogenic right ventricular cardiomyopathy, type 10; Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10; See all synonyms [MedGen]
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
SCV000038588OMIM
no assertion criteria provided
Pathogenic
(Mar 7, 2006)
germlineliterature only

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

SCV001404871Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 3, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy.

Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A.

Circulation. 2006 Mar 7;113(9):1171-9. Epub 2006 Feb 27.

PubMed [citation]
PMID:
16505173

Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.

Rigato I, Bauce B, Rampazzo A, Zorzi A, Pilichou K, Mazzotti E, Migliore F, Marra MP, Lorenzon A, De Bortoli M, Calore M, Nava A, Daliento L, Gregori D, Iliceto S, Thiene G, Basso C, Corrado D.

Circ Cardiovasc Genet. 2013 Dec;6(6):533-42. doi: 10.1161/CIRCGENETICS.113.000288. Epub 2013 Sep 26.

PubMed [citation]
PMID:
24070718
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000038588.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 sisters with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Pilichou et al. (2006) identified compound heterozygosity for a 991G-A transition in exon 8 of the DSG2 gene, resulting in a glu331-to-lys (E331K) substitution, and an A-to-G transition in the acceptor splice site of intron 12 of the DSG2 gene (1881-2A-G; 125671.0008). Sequence analysis of the aberrant DSG2 transcript from lymphocyte RNA of the 63-year-old proband showed that the latter mutation activates an alternative cryptic splice site in exon 13, predicted to result in a truncated 646-amino acid protein lacking the cytoplasmic domain. Their unaffected mother and an unaffected daughter of the proband were heterozygous for the E331K mutation, and a daughter with unknown disease status was heterozygous for the splice site mutation. The authors noted that although both mutations were potentially pathogenic, the possibility that the E331K mutation was a rare polymorphism could not be ruled out.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001404871.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 331 of the DSG2 protein (p.Glu331Lys). This variant is present in population databases (rs121913012, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 28471438, 30830208). ClinVar contains an entry for this variant (Variation ID: 16816). 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 not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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.

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

Last Updated: Sep 29, 2024