ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6062C>G (p.Ala2021Gly)

gnomAD frequency: 0.00003  dbSNP: rs760673242
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Total submissions: 5
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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 RCV000215746 SCV000271736 uncertain significance not specified 2015-04-16 criteria provided, single submitter clinical testing The p.Ala2021Gly variant in DSP has not been previously reported in individuals with cardiomyopathy, but been identified in 1/66550 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computation al prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala2021Gly varian t is uncertain.
GeneDx RCV000766953 SCV000571991 uncertain significance not provided 2017-07-24 criteria provided, single submitter clinical testing The A2021G variant of uncertain significance in the DSP gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A2021G variant of uncertain significance in the DSP gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A2021G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, this substitution occurs at a position that is not conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000621984 SCV000735860 uncertain significance Cardiovascular phenotype 2023-05-09 criteria provided, single submitter clinical testing The p.A2021G variant (also known as c.6062C>G), located in coding exon 24 of the DSP gene, results from a C to G substitution at nucleotide position 6062. The alanine at codon 2021 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a control cohort (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). 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 alteration remains unclear.
Invitae RCV000641794 SCV000763443 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-12-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001187340 SCV001354111 uncertain significance Cardiomyopathy 2023-06-16 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 2021 of the DSP 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 DSP-related disorders in the literature, but has been reported in one individual in a healthy control population (PMID: 31983221). This variant has been identified in 7/282288 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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