Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000485616 | SCV000565068 | pathogenic | not provided | 2017-03-21 | criteria provided, single submitter | clinical testing | The E63K pathogenic variant in the HRAS gene has been reported previously as a de novo variant in several unrelated individuals with congenital myopathy with excess muscle spindles (van der Burgt et al., 2007; Bolocan et al., 2014; Henry et al., 2015). The E63K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E63K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that E63K is associated with reduced intrinsic GTPase activity (Nur-E-Kamal et al., 1992). We interpret E63K as a pathogenic variant. |
Victorian Clinical Genetics Services, |
RCV002272015 | SCV002557413 | pathogenic | Costello syndrome | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome, congenital myopathy with excess of muscle spindles type (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four individuals, including two de novo events, in individuals described to have congenital myopathy, muscular dystrophy or muscle weakness (PMID: 17412879, 25070542, 26001911; ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies have demonstrated a reduction in GTP hydrolysis and subsequent inceased cell proliferation (PMID: 1362901, 8626650). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
OMIM | RCV000013442 | SCV000033689 | pathogenic | Myopathy, congenital, with excess of muscle spindles | 2007-07-01 | no assertion criteria provided | literature only |