NM_001943.5(DSG2):c.2110A>G (p.Ile704Val) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 28, 2023
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:: RCV003997673.2

Allele description [Variation Report for NM_001943.5(DSG2):c.2110A>G (p.Ile704Val)]

NM_001943.5(DSG2):c.2110A>G (p.Ile704Val)

Genes:

DSG2-AS1:DSG2 antisense RNA 1 [Gene - HGNC]
DSG2:desmoglein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_001943.5(DSG2):c.2110A>G (p.Ile704Val)

HGVS:

NC_000018.10:g.31542628A>G
NG_007072.3:g.49387A>G
NM_001943.5:c.2110A>GMANE SELECT
NP_001934.2:p.Ile704Val
LRG_397t1:c.2110A>G
LRG_397:g.49387A>G
NC_000018.9:g.29122591A>G
NM_001943.3:c.2110A>G
NM_001943.4:c.2110A>G

Protein change:

I704V

Links:

dbSNP: rs141388237

NCBI 1000 Genomes Browser:

rs141388237

Molecular consequence:

NM_001943.5:c.2110A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004821756	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Mar 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23396983, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004821756

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Mar 28, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.

Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, Jenkins S, McKenna W; Uk10k Consortium., Plagnol V, Elliott PM.

J Med Genet. 2013 Apr;50(4):228-39. doi: 10.1136/jmedgenet-2012-101270. Epub 2013 Feb 8.

PubMed [citation]

PMID:: 23396983
PMCID:: PMC3607113

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004821756.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces isoleucine with valine at codon 704 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic variant in the MYH7 gene (PMID: 23396983). This variant has been identified in 3/249432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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