Submissions for variant NM_004415.4(DSP):c.7066A>T (p.Lys2356Ter)

gnomAD frequency: 0.00001  dbSNP: rs1561703331

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760791	SCV000890686	likely pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Reported in association with ARVC (Wang et al., 2022); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34352074)
Fulgent Genetics, Fulgent Genetics	RCV002493387	SCV002802409	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117545	SCV003800972	likely pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: DSP c.7066A>T (p.Lys2356X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and observed in the HGMD database. The variant was absent in 251446 control chromosomes. c.7066A>T has been reported in the literature as a pathogenic variant in at-least one individual from the Johns Hopkins Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy registry (example, Wang_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003768287	SCV004611026	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-08-14	criteria provided, single submitter	clinical testing	This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (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. ClinVar contains an entry for this variant (Variation ID: 620416). This premature translational stop signal has been observed in individual(s) with DSP-related conditions (PMID: 34352074). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2356*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 516 amino acid(s) of the DSP protein. For these reasons, this variant has been classified as Pathogenic.