Submissions for variant NM_004415.4(DSP):c.8182dup (p.Glu2728fs)

dbSNP: rs1554109187

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003765113	SCV004583862	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2728Glyfs*11) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the DSP protein. 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: 199929). This variant disrupts a region of the DSP protein in which other variant(s) (p.Gln2730Serfs*16) have been determined to be pathogenic (PMID: 27532257, 28527814; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000181373	SCV000233674	not provided	not provided		no assertion provided	clinical testing	The c.8182dupG variant in the DSP gene has not been published as a pathogenic variant or as a benign polymorphism to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This nucleotide insertion causes a shift in reading frame beginning with Glutamic acid 2728, changing it to a Glycine, and creating a premature stop codon at position 11 of the new reading frame (p.Glu2728Glyfsx11). This variant is expected to result in an abnormal, truncated protein product.