Submissions for variant NM_004415.4(DSP):c.3415_3417delinsG (p.Tyr1139fs)

dbSNP: rs1064794616

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478280	SCV000569583	pathogenic	not provided	2017-01-20	criteria provided, single submitter	clinical testing	Although the c.3415_3417delTATinsG pathogenic variant in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Tyrosine 1139, changing it to a Glycine, and creating a premature stop codon at position 10 of the new reading frame, denoted p.Tyr1139GlyfsX10. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the DSP gene have been reported in HGMD in association with DSP-related disorders, including ARVC (Stenson et al., 2014). Furthermore, the c.3415_3417delTATinsG 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.
Invitae	RCV001241384	SCV001414398	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2019-08-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1139Glyfs*10) in the DSP gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related conditions. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). For these reasons, this variant has been classified as Pathogenic.