Submissions for variant NM_000540.3(RYR1):c.7976C>T (p.Thr2659Met)

gnomAD frequency: 0.00031  dbSNP: rs138325444

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000428395	SCV000536547	uncertain significance	not provided	2023-05-25	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
Invitae	RCV001239103	SCV001411952	uncertain significance	RYR1-related disorder	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2659 of the RYR1 protein (p.Thr2659Met). This variant is present in population databases (rs138325444, gnomAD 0.08%). 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: 393175). 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) has been performed at Invitae 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002481350	SCV002776057	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	2021-11-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000428395	SCV003813126	uncertain significance	not provided	2021-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317210	SCV004020717	uncertain significance	not specified	2023-06-08	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.7976C>T (p.Thr2659Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 282662 control chromosomes (gnomAD), predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (8.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.7976C>T in individuals affected with Malignant Hyperthermia Susceptibility and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.