ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6055G>T (p.Ala2019Ser)

dbSNP: rs771974957
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181385 SCV000233687 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing The A2019S variant of uncertain significance in the DSP gene has been reported in one Spanish individual with ARVC (Alcalde et al., 2014); however, detailed clinical information and segregation data were not provided. Although, the A2019S variant has been identified in another individual referred for ARVC testing at GeneDx, that individual also harbored a frameshift variant in another ARVC-related gene. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A2019S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the A2019S variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV001041422 SCV001205038 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2024-01-27 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001182506 SCV001347972 uncertain significance Cardiomyopathy 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 2019 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 right ventricular cardiomyopathy (PMID: 24967631). This variant has been identified in 11/282204 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.
Ambry Genetics RCV002354475 SCV002654623 uncertain significance Cardiovascular phenotype 2022-05-04 criteria provided, single submitter clinical testing The p.A2019S variant (also known as c.6055G>T), located in coding exon 24 of the DSP gene, results from a G to T substitution at nucleotide position 6055. The alanine at codon 2019 is replaced by serine, an amino acid with similar properties. This alteration was reported in an individual with arrhythmogenic right ventricular cardiomyopathy; however, no segregation information was available (Alcalde M et al. PLoS ONE, 2014 Jun;9:e100560). Another variant affecting this codon (p.A2019V, c.6056C>T) has been detected in a left ventricular non-compaction cohort (Miszalski-Jamka K et al. Circ Cardiovasc Genet. 2017 Aug;10(4)). This amino acid position is highly 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 alteration remains unclear.

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