Submissions for variant NM_001943.5(DSG2):c.1837G>A (p.Ala613Thr)

gnomAD frequency: 0.00004  dbSNP: rs368257724

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171904	SCV000050905	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037273	SCV000060930	uncertain significance	not specified	2012-10-19	criteria provided, single submitter	clinical testing	The Ala613Thr variant in DSG2 has been previously reported in one infant with DC M tested by our laboratory. This variant has been identified in 1/847 control ch romosomes (Kapplinger 2011) and in 1/4202 African American chromosomes from a br oad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/). Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the c linical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642324	SCV000763993	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 613 of the DSG2 protein (p.Ala613Thr). This variant is present in population databases (rs368257724, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 44288). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color Diagnostics, LLC DBA Color Health	RCV001179085	SCV001343675	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 613 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 DSG2-related disorders in the literature. This variant has been identified in 5/280334 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.
GeneDx	RCV000171904	SCV001985816	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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: 21636032)
All of Us Research Program, National Institutes of Health	RCV003996308	SCV004819577	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces alanine with threonine at codon 613 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 5/280334 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	RCV004018833	SCV004859459	uncertain significance	Cardiovascular phenotype	2022-07-19	criteria provided, single submitter	clinical testing	The c.1837G>A (p.A613T) alteration is located in exon 12 (coding exon 12) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 1837, causing the alanine (A) at amino acid position 613 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.