ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14344G>A (p.Gly4782Arg) (rs746538672)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725566 SCV000337845 uncertain significance not provided 2015-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000725566 SCV000589775 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing The G4782R variant in the RYR1 gene has been reported previously in the compound heterozygous state in patient who presented with cystic hygroma, abnormal skull, club feet and poor movement, diagnosed with congenital myopathy/fetal akinesia (Westerfield et al., 2015). The G4782R variant is observed in 1/9426 (0.011%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G4782R 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G4782R as a variant of uncertain significance.
Invitae RCV001042937 SCV001206646 pathogenic RYR1-Related Disorders 2019-06-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 4782 of the RYR1 protein (p.Gly4782Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs746538672, ExAC 0.01%). This variant has been observed in combination with another RYR1 variant in pregnancies and infants affected with congenital myopathy and fetal akinesia (PMID: 26275793, 29096039). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant, which is consistent with autosomal recessive inheritance. ClinVar contains an entry for this variant (Variation ID: 285009). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). For these reasons, this variant has been classified as Pathogenic.

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