ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.908C>T (p.Ser303Phe)

gnomAD frequency: 0.00001  dbSNP: rs757792714
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000477384 SCV000551010 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 303 of the DSG2 protein (p.Ser303Phe). This variant is present in population databases (rs757792714, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 410368). 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.
Color Diagnostics, LLC DBA Color Health RCV001186045 SCV001352383 uncertain significance Cardiomyopathy 2021-03-25 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 303 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 an individual affected with arrhythmogenic cardiomyopathy (PMID: 32268277). This variant has been identified in 2/249400 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 RCV001550730 SCV001771110 uncertain significance not provided 2020-12-16 criteria provided, single submitter clinical testing Identified in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) in published literature (Walsh et al., 2017); 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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#410368; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31402444, 27532257)
Fulgent Genetics, Fulgent Genetics RCV002481458 SCV002783934 uncertain significance Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB 2021-07-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV003298496 SCV003989519 uncertain significance Cardiovascular phenotype 2023-04-27 criteria provided, single submitter clinical testing The p.S303F variant (also known as c.908C>T), located in coding exon 8 of the DSG2 gene, results from a C to T substitution at nucleotide position 908. The serine at codon 303 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004806317 SCV005428692 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 303 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 an individual affected with arrhythmogenic cardiomyopathy (PMID: 32268277). This variant has been identified in 2/249400 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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