Submissions for variant NM_000540.3(RYR1):c.6385G>A (p.Asp2129Asn)

gnomAD frequency: 0.00004  dbSNP: rs772695891

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691284	SCV000819036	uncertain significance	RYR1-related disorder	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2129 of the RYR1 protein (p.Asp2129Asn). This variant is present in population databases (rs772695891, gnomAD 0.05%). This missense change has been observed in individual(s) with RYR1-related conditions (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 570420). 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	RCV001592879	SCV001823856	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28326467, 25960145, 27663056, 30788618, 23628358, 12668474)
Fulgent Genetics, Fulgent Genetics	RCV002493173	SCV002784080	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	2021-09-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001592879	SCV003812406	uncertain significance	not provided	2019-03-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999555	SCV004820875	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2129 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature, although is has been observed in an individual affected with exercise induced rhabdomyolysis (PMID: 25960145). This variant has been identified in 10/281482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.6387C>G (p.Asp2129Glu), is considered to be pathogenic (ClinVar Variation ID: 133157), suggesting that Asp at this position is important for the protein function. 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.