Submissions for variant NM_000540.3(RYR1):c.13313T>G (p.Val4438Gly)

gnomAD frequency: 0.00002  dbSNP: rs1328605630

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV002507265	SCV002814488	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	2021-08-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003106038	SCV003782354	uncertain significance	RYR1-related disorder	2024-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4438 of the RYR1 protein (p.Val4438Gly). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 590429). 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 with a negative predictive value of 95%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000721312	SCV004183655	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	RYR1: PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056476	SCV005725648	uncertain significance	not specified	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13313T>G (p.Val4438Gly) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 (IPR009460) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 13588 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13313T>G has been reported in the literature in individuals affected with Malignant hyperthermia (Roux-Buisson_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26994242). ClinVar contains an entry for this variant (Variation ID: 590429). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003106038	SCV000852343	uncertain significance	RYR1-related disorder	2023-12-13	no assertion criteria provided	clinical testing	The RYR1 c.13313T>G variant is predicted to result in the amino acid substitution p.Val4438Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.