Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001386285 | SCV001586462 | pathogenic | not provided | 2021-02-13 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 672 of the MYH3 protein (p.Arg672Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been reported in several individuals affected with Freeman-Sheldon syndrome, including some in which the variant was found to be de novo (PMID: 16642020, 20924721, 25256237, 25740846). ClinVar contains an entry for this variant (Variation ID: 14139). Experimental studies have shown that this missense change alters MYH3 kinetic properties in skeletal muscle cells (PMID: 25740846, 26945064). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001386285 | SCV002032716 | pathogenic | not provided | 2022-06-13 | criteria provided, single submitter | clinical testing | Published functional studies in Drosophila demonstrate that this variant reduces ATPase activity and causes abnormal muscle structure and function (Rao et al., 2019; Das et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32714615, 28584669, 25740846, 30826400, 26180627, 31966463, 26494722, 25957469, 31085342, 29625835, 31746383, 28205584, 20924721, 30379605, 26275891, 16642020) |
| Victorian Clinical Genetics Services, |
RCV000015201 | SCV005399576 | pathogenic | Freeman-Sheldon syndrome | 2023-07-16 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B (CPSFS1B; MIM#618469). While functional studies support a loss of function mechanism for missense variants causing arthrogryposis, distal, type 2A (Freeman-Sheldon) (DA2A; MIM#193700), arthrogryposis, distal, type 2B (Sheldon-Hall) (DA2B; MIM#618436) or contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A (CPSFS1A, MIM#178110), dominant negative has not been excluded as a mechanism (PMID: 26945064). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with CPSFS1B have a second hit in the 5' UTR region which affects splicing and is regarded as a hypomorphic allele. Missense variants and inframe variants have been reported for dominant disease (PMID: 29805041, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with the same variant present with varying severity (PMID: 29805041). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin head (motor) domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic, and observed in both de novo and familial cases of Freeman-Sheldon syndrome (ClinVar, PMID: 20924721, PMID: 25256237). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000015201 | SCV000035458 | pathogenic | Freeman-Sheldon syndrome | 2006-05-01 | no assertion criteria provided | literature only |