Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788294 | SCV005399483 | uncertain significance | X-linked myopathy with postural muscle atrophy | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Emery-Dreifuss muscular dystrophy 6 (MIM#300696; PMID: 19716112). The mechanism of disease for other FHL1-related conditions is unclear (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene has been reported in both carrier and clinically affected females (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable muscle weakness has been reported for Emery-Dreifuss muscular dystrophy 6 (MIM#300696; PMID: 31840275). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to glutamine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional 4th LIM domain, within a zinc ion coordinating histidine residue (PMID: 19687455). (SP) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.(His262Tyr)) has been reported as a VUS, but also described in two unrelated hemizygous individuals with X-linked myopathy with postural muscle atrophy and generalized hypertrophy (ClinVar, PMID: 19687455, PMID: 22923418). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been described as a VUS and observed in an individual with hypertrophic cardiomyopathy (ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |