Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000221238 | SCV000271620 | uncertain significance | not specified | 2015-02-20 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile123fs variant in DES has not been previously reported in individuals with cardiomyopat hy, but has been identified in at least 2 South Asian chromosomes by the Exome A ggregation Consortium. However, data from large population studies is insufficie nt to assess the frequency of this variant (ExAC, http://exac.broadinstitute.org ). This variant is predicted to cause a frameshift, which alters the protein?s a mino acid sequence beginning at position 123 and leads to a premature terminatio n codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating DES variants have been reported in a n umber of individuals with a range of phenotypes including myopathy, DCM, HCM, an d/or conduction system disease (Park 2000, Dalakas 2000, Schroder 2003, Dunand 2 009, Hong 2010, Wahbi 2012, McLaughlin 2013) and both dominant and recessive mod es of inheritance have been described (Dunand 2009, Wahbi 2012, McLaughlin 2013) . However, the effect of truncating variants in the DES gene has not been fully elucidated. In summary, while there is some suspicion for a pathogenic role, th e clinical significance of the p.Ile123fs variant is uncertain. |
| Labcorp Genetics |
RCV001853441 | SCV002232133 | pathogenic | Desmin-related myofibrillar myopathy | 2023-05-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ile123Metfs*18) in the DES gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228548). This variant has not been reported in the literature in individuals affected with DES-related conditions. This variant is present in population databases (rs747289875, gnomAD 0.008%). |