Submissions for variant NM_004415.4(DSP):c.4423del (p.Thr1475fs)

dbSNP: rs1227662860

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816850	SCV000957377	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1475Profs*9) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 659795). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003166362	SCV003867570	pathogenic	Cardiovascular phenotype	2022-12-23	criteria provided, single submitter	clinical testing	The c.4423delA pathogenic mutation, located in coding exon 23 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 4423, causing a translational frameshift with a predicted alternate stop codon (p.T1475Pfs*9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV004822224	SCV005443214	likely pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with dilated cardiomyopathy in published literature (PMID: 36580316); This variant is associated with the following publications: (PMID: 36580316)
Color Diagnostics, LLC DBA Color Health	RCV005401626	SCV006062246	pathogenic	Cardiomyopathy	2024-04-29	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 23 of the DSP gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, 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). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.