Submissions for variant NM_000540.3(RYR1):c.11269A>G (p.Met3757Val)

gnomAD frequency: 0.00005  dbSNP: rs189249768

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001248213	SCV001421683	uncertain significance	RYR1-related disorder	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3757 of the RYR1 protein (p.Met3757Val). This variant is present in population databases (rs189249768, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 972231). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252343	SCV002523451	uncertain significance	See cases	2020-01-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2
Fulgent Genetics, Fulgent Genetics	RCV002484395	SCV002785845	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003130232	SCV003812456	uncertain significance	not provided	2021-11-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323832	SCV004028793	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.11269A>G (p.Met3757Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250684 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4.8e-05 vs 8.8e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.11269A>G in individuals affected with Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003130232	SCV005081396	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge