ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1493C>T (p.Pro498Leu)

gnomAD frequency: 0.00002  dbSNP: rs761051181
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001063474 SCV001228321 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-12-18 criteria provided, single submitter clinical testing
3billion RCV001809974 SCV002058991 uncertain significance Woolly hair-skin fragility syndrome 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DSP related disorder (PMID:26148547, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.646, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001809974 SCV002818533 uncertain significance Woolly hair-skin fragility syndrome 2023-01-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003532368 SCV004363299 uncertain significance Cardiomyopathy 2022-06-15 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 498 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a large family segregating with an autosomal recessive form of hair loss disorder (PMID: 26148547). There was no history of sudden death in this family and the three affected homozygotes were reported to be normal in cardiac auscultation and echocardiographic evaluation. This variant has been identified in 4/251448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant heart disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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