rs121913012
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001943.5(DSG2):c.991G>A(p.Glu331Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.991G>A | p.Glu331Lys | missense_variant | Exon 8 of 15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
DSG2 | ENST00000682087.2 | n.822G>A | non_coding_transcript_exon_variant | Exon 6 of 6 | ||||||
DSG2 | ENST00000683614.2 | n.822G>A | non_coding_transcript_exon_variant | Exon 6 of 7 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249402Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135310
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461842Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 727222
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:2
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193). (I) 0107 - This gene is associated with autosomal dominant disease. It is commonly associated with dominant inheritance for arrhythmogenic right ventricular dysplasia 10 (MIM#610193). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cadherin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported five times in ClinVar as a VUS and reported in the literature as a VUS in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 29750433, 28471438). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was identified in two affected siblings both also compound heterozygous for a splice site variant. The two children of one of these siblings both carry the missense variant and no splice site variant, these two individuals are either unaffected or of unknown disease status (PMID: 16505173). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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. -
Cardiomyopathy Uncertain:2
This missense variant replaces glutamic acid with lysine at codon 331 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 16505173, 21606390, 29750433) and in three unaffected relatives from one of the families (PMID: 16505173, 24070718, 26138720). One of the probands was compound heterozygous with a splice variant (PMID 26138720). This variant has been identified in 4/249402 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. -
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Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
The c.991G>A (p.Glu331Lys) missense variant changes evolutionary conserved Glu to Lys, which changes the charge from negative to positive. 3/4 in silico tools predict this variant to be damaging. This variant lies in cadherin 3 domain (source ARVC db) and other missense changes have also been detected in and around this codon such as p.D326V, p.N330D, p.I333T and p.T335A (source: HGMD) in ARVC patients. This suggests that this variant may alter protein functionality. The variant is found in only 3 alleles across 120630 chromosomes in ExAC. Although the allele frequency in general population is lower than the maximal expected allele frequency based on the disease prevalence of ARVC, the possibility of this variant being a rare polymorphism cannot be ruled out. Two studies reported this variant in two ARVD families; however, segregation analysis in one family does not prove the variant as a high penetrance disease-causing variant. -
This missense variant replaces glutamic acid with lysine at codon 331 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 16505173, 21606390, 29750433) and in three unaffected relatives from one of the families (PMID: 16505173, 24070718, 26138720). One of the probands was compound heterozygous with a splice variant (PMID 26138720). This variant has been identified in 4/249402 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. -
not provided Uncertain:1
Identified in two siblings with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, both individuals also harbor a splice site variant in the DSG2 gene (Pilichou et al., 2006); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 16816; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 16505173) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at