Submissions for variant NM_000540.3(RYR1):c.8113G>A (p.Ala2705Thr)

gnomAD frequency: 0.00003  dbSNP: rs536813036

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210029	SCV000265725	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Invitae	RCV000689719	SCV000817384	uncertain significance	RYR1-related disorder	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2705 of the RYR1 protein (p.Ala2705Thr). This variant is present in population databases (rs536813036, gnomAD 0.008%). 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: 224392). 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.
Illumina Laboratory Services, Illumina	RCV001128009	SCV001287390	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000210029	SCV001287391	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV002500675	SCV002777583	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	2021-09-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000210029	SCV004818065	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2705 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 9/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.