Submissions for variant NM_000540.3(RYR1):c.10561G>A (p.Gly3521Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058757	SCV003448890	likely pathogenic	RYR1-related disorder	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3521 of the RYR1 protein (p.Gly3521Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 29382405, 31130284). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.10546G>A; p.Gly3516Ser. ClinVar contains an entry for this variant (Variation ID: 2141851). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. This variant disrupts the p.Gly3521 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 21062345), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003447639	SCV004175798	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2023-02-14	criteria provided, single submitter	clinical testing	The missense variant c.10561G>A (p.Gly3521Ser) in the RYR1 gene has been reported previously in compound heterozygous state in an individual affected with Congenital Myopathy (Bevilacqua et al., 2011). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic. However, study on multiple affected individuals and the functional impact of the variant is not available. The amino acid Glycine at position 3521 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gly3521Ser in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.