Submissions for variant NM_004415.4(DSP):c.6273del (p.Ala2092fs)

dbSNP: rs794728146

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181369	SCV000233670	pathogenic	not provided	2019-10-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift 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 (Lek et al., 2016)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195306	SCV001365631	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2020-02-10	criteria provided, single submitter	clinical testing	The p.Ala2092LeufsX24 variant in DSP has not been previously reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) or Carvajal syndrome but has been reported by other clinical laboratories in ClinVar (Variation ID #545955). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2029 and leads to a premature termination codon 24 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~25% of the coding region, with 756 amino acids removed. Additional truncating variants downstream of this variant have been reported in individuals with ARVC/ Carvajal syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC and autosomal recessive Carvajal syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001842797	SCV001467874	likely pathogenic	Cardiac arrhythmia	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: DSP c.6273delA (p.Ala2092LeufsX24) 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. The variant was absent in 251392 control chromosomes. To our knowledge, no occurrence of c.6273delA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported in the literature, however the variant has been reported in individuals referred for cardiomyopathy genetic testing by other laboratories in ClinVar. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014); both cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001382194	SCV001580850	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala2092Leufs*24) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 780 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: 199925). 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. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542756	SCV001760189	likely pathogenic	Arrhythmogenic right ventricular dysplasia 8		no assertion criteria provided	clinical testing