ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.308T>C (p.Val103Ala)

gnomAD frequency: 0.00001  dbSNP: rs876657790
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000219672 SCV000271711 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing The p.Val103Ala variant in DSG2 has been identified by our laboratory in one ind ividual with DCM and segregated with disease in one affected relative. Both of t hese individuals also carried a likely pathogenic variant in a different gene su fficient to cause disease. The p.Val103Ala has not been previously reported in t he literature and is absent from large population studies. Valine (Val) at posit ion 103 is not conserved in mammals or evolutionarily distant species and 1 mamm al (big brown bat) carries an alanine (Ala), raising the possibility that this c hange may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinica l significance of the p.Val103Ala variant is uncertain.
Color Diagnostics, LLC DBA Color Health RCV000771963 SCV000904917 uncertain significance Cardiomyopathy 2023-10-10 criteria provided, single submitter clinical testing This missense variant replaces valine with alanine at codon 103 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 been reported in at least one individual affected with dilated cardiomyopathy (PMID: 31983221; ClinVar: SCV000271711.2) and in one individual with Diamond-Blackfan anemia type 1 with sinus bradycardia who also carried a pathogenic variant in the RPS19 gene (PMID: 36837563). This variant has been identified in 1/249158 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.
Invitae RCV001853447 SCV002211196 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-11-08 criteria provided, single submitter clinical testing This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 103 of the DSG2 protein (p.Val103Ala). 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. 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. ClinVar contains an entry for this variant (Variation ID: 228627). This variant has not been reported in the literature in individuals affected with DSG2-related conditions.
Ambry Genetics RCV002321839 SCV002606372 uncertain significance Cardiovascular phenotype 2015-11-24 criteria provided, single submitter clinical testing The p.V103A variant (also known as c.308T>C), located in coding exon 4 of the DSG2 gene, results from a T to C substitution at nucleotide position 308. The valine at codon 103 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5872 samples (11744 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

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