Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000532704 | SCV000639743 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2018-05-17 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the DSP gene (p.Val1821Serfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1051 amino acids of the DSP protein. 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 disease. A different truncation (p.Ser2168Argfs*18) that lies downstream of this variant has been determined to be pathogenic (Invitae). This suggests that deletion of this region of the DSP protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786117 | SCV000924777 | likely pathogenic | not provided | 2017-06-21 | no assertion criteria provided | provider interpretation | This variant was identified in a patient with DCM and cardiac arrest. Given the variant type and absence in control populations, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This is a novel variant and does not have an entry in ClinVar. However, the majority of the mutations in the DSP gene associated with ARVC in HGMD are nonsense or frameshifts mutations (Stenson P et al., 2009). Of the reported nonsense and frameshift variants, several have been reported downstream of this variant, suggesting that this is a critical region of the protein. Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000) and cardiodb.org lists truncating variants in DSP enriched both cases of ARVC and DCM vs. controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. The c-terminal end of the protein, which is altered by this frameshift, is important for protein interactions with IFs to anchor them to the desmosome (Kouklis et al. 1994; Bornslaeger et al. 1996). Groeneweg et al. (2016) reports on 1001 ARVC index patients from the Hopkins cohort. Nine of eleven index patients have either nonsense or frameshift variants in the DSP gene. This variant is absent in both ExAC and gnomAD. This site is well covered in both databases (>70X). Together, these databases includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. |