Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001050426 | SCV001214533 | uncertain significance | Epileptic encephalopathy | 2019-03-07 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR3-related conditions. This variant is present in population databases (rs763223227, ExAC 0.01%). This sequence change replaces arginine with cysteine at codon 3048 of the RYR3 protein (p.Arg3048Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387957 | SCV004099896 | uncertain significance | not specified | 2023-09-16 | criteria provided, single submitter | clinical testing | Variant summary: RYR3 c.9142C>T (p.Arg3048Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 247994 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9142C>T has been reported in the literature in at least one compound heterozygous individual affected with Autism Spectrum Disorder (e.g., Nguyen_2016, no PMID). This report does not provide unequivocal conclusions about association of the variant with Congenital Myopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |