ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6185A>G (p.His2062Arg)

dbSNP: rs730880086
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
All of Us Research Program, National Institutes of Health RCV003998333 SCV004816722 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 2062 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. This variant has not been identified 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 RCV004719721 SCV005326250 uncertain significance not provided 2024-01-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28416588)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004786417 SCV005398692 uncertain significance Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ARVC (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29062697). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated plectin repeat (NCBI, DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS in ClinVar and as a possibly pathogenic rare variant in an individual with dilated cardiomyopathy (PMID: 28416588). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Blueprint Genetics RCV000157204 SCV000206928 uncertain significance Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing

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