ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4303G>C (p.Ala1435Pro)

gnomAD frequency: 0.00001  dbSNP: rs751972271
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641773 SCV000763421 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175481 SCV001339074 uncertain significance not specified 2020-03-11 criteria provided, single submitter clinical testing Variant summary: DSP c.4303G>C (p.Ala1435Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4303G>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. At least one co-occurrence with another pathogenic variant has been internally reported (TTN c.85692_85696delAGCTT, p.Trp28566X), providing supporting evidence for a benign role. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001180336 SCV001345244 uncertain significance Cardiomyopathy 2023-04-25 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 1435 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 been reported in an individual affected with sudden cardiac death and idiopathic left ventricular hypertrophy at autopsy (PMID: 31534214). This variant has been identified in 3/251410 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 RCV001771873 SCV001992676 uncertain significance not provided 2019-06-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31534214)
Fulgent Genetics, Fulgent Genetics RCV002492999 SCV002789442 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis 2021-09-09 criteria provided, single submitter clinical testing

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