Submissions for variant NM_004415.4(DSP):c.4610G>A (p.Arg1537His)

gnomAD frequency: 0.00002  dbSNP: rs762135558

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773624	SCV000907318	uncertain significance	Cardiomyopathy	2023-08-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1537 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 been identified in 5/250282 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265878	SCV002548320	uncertain significance	not specified	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4610G>A (p.Arg1537His) 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 2e-05 in 250282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4610G>A has been reported in the literature in at-least one individual within a cohort of Hypertrophic Cardiomyopathy with mid-ventricular obstruction (HCM-MVO) subtype, who underwent a multigene panel testing for 67 known cardiomyopathy associated genes associated with secondary cardiomyopathy (example, Inagaki_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002536656	SCV002939075	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003307407	SCV003996582	uncertain significance	Cardiovascular phenotype	2023-04-17	criteria provided, single submitter	clinical testing	The p.R1537H variant (also known as c.4610G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4610. The arginine at codon 1537 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a subject with asymmetric hypertrophy, and apical aneurysm (Inagaki N et al. J Hum Genet, 2018 Dec;63:1273-1276). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004000028	SCV004823987	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1537 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 cardiovascular disorders in the literature. This variant has been identified in 5/250282 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.