rs730880347

Positions:

• chr18-31536264-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001943.5(DSG2):​c.1487dup​(p.Cys496TrpfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSG2 NM_001943.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.64

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31536264-T-TG is Pathogenic according to our data. Variant chr18-31536264-T-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178852.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.1487dup	p.Cys496TrpfsTer40	frameshift_variant	11/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.953dup	p.Cys318TrpfsTer40	frameshift_variant	12/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.1487dup	p.Cys496TrpfsTer40	frameshift_variant	11/15	1	NM_001943.5	ENSP00000261590	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). This variant has not been reported in the literature in individuals with DSG2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys496Trpfs*40) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has been reported in one individual from the eMERGE healthy exome study (PMID: 31638835); This variant is associated with the following publications: (PMID: 31638835) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The c.1487dupG pathogenic mutation, located in coding exon 11 of the DSG2 gene, results from a duplication of G at nucleotide position 1487, causing a translational frameshift with a predicted alternate stop codon (p.C496Wfs*40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys496fs variant in DSG2 has been identified by our laboratory in 1 Caucasian individual with possible ARVC including biventricular dilation and VT; however this individ ual also carried a likely pathogenic variant in TTN. The p.Cys496fs variant was absent from large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 496 and leads to a premature termination codon 40 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Frameshift and other loss of function variants in DSG2 gene have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Cys496fs variant is uncertain. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 03, 2023

This variant causes a duplication of one nucleotide in exon 11 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 13 individuals from a cohort of participants undergoing whole exome sequencing (PMID: 31638835). None of these individuals had an existing diagnosis of arrhythmogenic right ventricular cardiomyopathy or abnormal ECG or echocardiogram findings. This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880347; hg19: chr18-29116227;