Submissions for variant NM_001943.5(DSG2):c.2960T>C (p.Val987Ala)

gnomAD frequency: 0.00003  dbSNP: rs727502991

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150547	SCV000197775	uncertain significance	not specified	2018-09-05	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Color Diagnostics, LLC DBA Color Health	RCV001188345	SCV001355382	uncertain significance	Cardiomyopathy	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 987 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/279952 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850044	SCV002113890	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2021-01-07	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 163223). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 987 of the DSG2 protein (p.Val987Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
Fulgent Genetics, Fulgent Genetics	RCV002483304	SCV002785572	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-07-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998194	SCV004821859	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic desmoglein repeat 4 of the DSG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/276188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Ambry Genetics	RCV004019807	SCV005018369	uncertain significance	Cardiovascular phenotype	2024-02-26	criteria provided, single submitter	clinical testing	The p.V987A variant (also known as c.2960T>C), located in coding exon 15 of the DSG2 gene, results from a T to C substitution at nucleotide position 2960. The valine at codon 987 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.