Submissions for variant NM_004415.4(DSP):c.6456dup (p.Leu2153fs)

dbSNP: rs1554108854

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479310	SCV000572151	likely pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing	Although the c.6456dupG likely pathogenic variant in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon leucine 2153, changing it to an alanine, and creating a premature stop codon at position 3 of the new reading frame, denoted p.Leu2153AlafsX3. This likely pathogenic variant is expected to result in an abnormal, truncated protein product as the last 719 amino acids are replaced with two incorrect amino acids. Other downstream frameshift variants in the DSP gene have been reported in HGMD in association with DSP-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.6456dupG variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae	RCV002526634	SCV003218155	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-06-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (PMID: 21859740, 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. ClinVar contains an entry for this variant (Variation ID: 422637). 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.Leu2153Alafs*3) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 719 amino acid(s) of the DSP protein.