Submissions for variant NM_004415.4(DSP):c.4999C>T (p.Gln1667Ter)

dbSNP: rs1554108431

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578658	SCV000680948	pathogenic	not provided	2023-04-29	criteria provided, single submitter	clinical testing	Nonsense 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); This variant is associated with the following publications: (PMID: 33684294, 31638835, 31447099, Reza_2022_Cardiogenetics)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612029	SCV000731568	likely pathogenic	Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy	2017-05-11	criteria provided, single submitter	clinical testing	The p.Gln1667X variant in DSP has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This variant is located within exon 23 of DSP which undergoes alternative splicing resulting in two isoforms: one with a shorter and one with a longer form of this exon. This variant is only located in the coding region of the longer isoform. In that transcript, this no nsense variant leads to a premature termination codon at position 1667, which is predicted to lead to a truncated or absent protein. Loss-of-function variants i n the longer form of exon 23 have been observed in individuals with ARVC and/or DCM, suggesting that loss-of-function variants in this region are likely to be d isease causing (LMM data). In summary, although additional studies are required to fully establish its clinical significance, the p.Gln1667X variant is likely p athogenic.
Invitae	RCV000692483	SCV000820308	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 488983). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1667*) 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).
Baylor Genetics	RCV001332446	SCV001524774	likely pathogenic	Woolly hair-skin fragility syndrome	2020-06-08	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].