Submissions for variant NM_000540.3(RYR1):c.14915C>T (p.Thr4972Ile)

gnomAD frequency: 0.00006  dbSNP: rs199866740

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000209974	SCV000265752	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Invitae	RCV000541881	SCV000659863	uncertain significance	RYR1-related disorder	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 4972 of the RYR1 protein (p.Thr4972Ile). This variant is present in population databases (rs199866740, 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: 224407). 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. 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	RCV001582718	SCV001812832	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 D4967E 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; This variant is associated with the following publications: (PMID: 25214167)
Fulgent Genetics, Fulgent Genetics	RCV002485369	SCV002778369	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	2022-02-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001582718	SCV003814997	uncertain significance	not provided	2020-08-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000209974	SCV004816281	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 4972 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 22/282792 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.