NM_001943.5(DSG2):c.464_465insT (p.Glu156fs) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 10, 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:: RCV003996625.2

Allele description [Variation Report for NM_001943.5(DSG2):c.464_465insT (p.Glu156fs)]

NM_001943.5(DSG2):c.464_465insT (p.Glu156fs)

Gene:

DSG2:desmoglein 2 [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_001943.5(DSG2):c.464_465insT (p.Glu156fs)

HGVS:

NC_000018.10:g.31521184_31521185insT
NG_007072.3:g.27943_27944insT
NM_001943.5:c.464_465insTMANE SELECT
NP_001934.2:p.Glu156fs
LRG_397t1:c.464_465insT
LRG_397:g.27943_27944insT
NC_000018.9:g.29101147_29101148insT
NM_001943.3:c.464_465insT
p.E156RfsX14

Protein change:

E156fs

Links:

dbSNP: rs794728091

NCBI 1000 Genomes Browser:

rs794728091

Molecular consequence:

NM_001943.5:c.464_465insT - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004830611	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25616645, 31386562, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004830611

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 10, 2023)

germline

clinical testing

PubMed (3)
[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

Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers.

Bhonsale A, Groeneweg JA, James CA, Dooijes D, Tichnell C, Jongbloed JD, Murray B, te Riele AS, van den Berg MP, Bikker H, Atsma DE, de Groot NM, Houweling AC, van der Heijden JF, Russell SD, Doevendans PA, van Veen TA, Tandri H, Wilde AA, Judge DP, van Tintelen JP, Calkins H, et al.

Eur Heart J. 2015 Apr 7;36(14):847-55. doi: 10.1093/eurheartj/ehu509. Epub 2015 Jan 23.

PubMed [citation]

PMID:: 25616645

Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.

van Lint FHM, Murray B, Tichnell C, Zwart R, Amat N, Lekanne Deprez RH, Dittmann S, Stallmeyer B, Calkins H, van der Smagt JJ, van den Wijngaard A, Dooijes D, van der Zwaag PA, Schulze-Bahr E, Judge DP, Jongbloed JDH, van Tintelen JP, James CA.

Circ Genom Precis Med. 2019 Aug;12(8):e002467. doi: 10.1161/CIRCGEN.119.002467. Epub 2019 Aug 6.

PubMed [citation]

PMID:: 31386562

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004830611.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This variant inserts 1 nucleotide in exon 5 of the DSG2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individual(s) affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 25616645, 31386562). This variant has been identified in 1/249316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. 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: May 7, 2024

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