Submissions for variant NM_000540.3(RYR1):c.14901C>G (p.Asp4967Glu)

gnomAD frequency: 0.00006  dbSNP: rs201712715

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210027	SCV000265751	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Invitae	RCV000524607	SCV000659862	uncertain significance	RYR1-related disorder	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 4967 of the RYR1 protein (p.Asp4967Glu). This variant is present in population databases (rs201712715, gnomAD 0.02%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 25214167). ClinVar contains an entry for this variant (Variation ID: 224406). 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.
GeneDx	RCV001569875	SCV001794036	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing	Reported in a patient with limb-girdle muscular dystrophy who also harbors the T4972I variant in the RYR1 gene in the published literature (Savarese et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25214167)
Fulgent Genetics, Fulgent Genetics	RCV002500680	SCV002785955	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	2021-08-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001569875	SCV003812477	uncertain significance	not provided	2020-08-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000210027	SCV004816279	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 4967 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with limb-girdle muscular dystrophy (PMID: 25214167). This variant has been identified in 22/282814 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.