Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001071703 | SCV001237021 | uncertain significance | RYR1-Related Disorders | 2023-09-19 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 864497). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs749718772, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3300 of the RYR1 protein (p.Ala3300Val). |
| Department of Pathology and Laboratory Medicine, |
RCV001355156 | SCV001549951 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The RYR1 p.Ala3300Val variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs749718772) and in control databases in 5 of 278998 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24758 chromosomes (freq: 0.00004) and European (non-Finnish) in 4 of 125900 chromosomes (freq: 0.000032), but not in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Ala3300 residue is not conserved in mammals and five out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |