Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Blueprint Genetics | RCV000157216 | SCV000206940 | likely pathogenic | Cardiomyopathy | 2015-01-08 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000157216 | SCV001734693 | likely pathogenic | Cardiomyopathy | 2020-12-16 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in the expression of a truncated protein product lacking C-terminal plakin repeat domains that bind intermediate filaments. This variant has been reported in heterozygous state in ten unrelated Finnish individuals (PMID: 26084686, 32005173), including nine individuals affected with dilated cardiomyopathy and one affected individual with slightly dilated ventricles. Subsequently, seven additional family members have been identified to carry this variant. Four of these individuals were affected with dilated cardiomyopathy or other cardiac abnormalities, and three individuals were unaffected. Furthermore, most of the carriers with dilated cardiomyopathy showed an arrhythmogenic phenotype (PMID: 32005173). This variant has also been reported in the compound heterozygous state with another truncation or missense variant in two individuals affected with severe cardiomyopathies and skin, hair, and/or tooth abnormalities (PMID: 19924139, 24341478). Desmoplakin was either not expressed or reduced in skin biopsies from the two individuals. Heterozygous family members were unaffected in both families. This variant has been identified in 13/251432 chromosomes (11/21648 Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Multiple truncations variants that lie downstream of this variant are known to cause arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy (ClinVar). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Invitae | RCV003764988 | SCV004569798 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr2104Glnfs*12) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 768 amino acid(s) of the DSP protein. This variant is present in population databases (rs730880092, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 19924139, 24341478, 35653365). ClinVar contains an entry for this variant (Variation ID: 180343). 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. |
| OMIM | RCV003234551 | SCV003931137 | pathogenic | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma | 2023-06-12 | no assertion criteria provided | literature only |