Submissions for variant NM_000540.3(RYR1):c.9811G>A (p.Glu3271Lys)

gnomAD frequency: 0.00003  dbSNP: rs773026490

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203097	SCV001374243	uncertain significance	RYR1-related disorder	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3271 of the RYR1 protein (p.Glu3271Lys). This variant is present in population databases (rs773026490, gnomAD 0.009%). This missense change has been observed in individual(s) with multiminicore disease (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 934660). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508859	SCV001715276	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001508859	SCV002028108	likely pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing	Identified on the same allele (in cis) with another RYR1 variant and inherited from an unaffected parent in a patient with multiminicore disease in published literature (Snoeck et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25960145)
All of Us Research Program, National Institutes of Health	RCV004010624	SCV004820962	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 3271 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function.. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 934660). This variant has been identified in 5/281938 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690011	SCV005184725	uncertain significance	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.9811G>A (p.Glu3271Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250630 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9811G>A has been reported in the literature in at least one individual affected with myopathy who also had a second missense variant of uncertain significance in cis (on the same chromosome) (e.g. Snoeck_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Multicore Myopathy With External Ophthalmoplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 934660). Based on the evidence outlined above, the variant was classified as uncertain significance.