Submissions for variant NM_000540.3(RYR1):c.14423T>A (p.Phe4808Tyr)

dbSNP: rs1274780855

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002035647	SCV002278986	pathogenic	RYR1-related disorder	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 4808 of the RYR1 protein (p.Phe4808Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR1-related conditions (PMID: 23394784, 32381727). ClinVar contains an entry for this variant (Variation ID: 1498872). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Phe4808 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12565913, 21455645, 27447704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV002283577	SCV002573199	likely pathogenic	Central core myopathy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RYR1-related disorder (ClinVar ID: VCV001498872 / PMID: 23394784). Different missense changes at the same codon (p.Phe4808Asn, p.Phe4808Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000478199 , VCV001213684). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
All of Us Research Program, National Institutes of Health	RCV004804342	SCV005426525	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 4808 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. 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. It has been observed in two individuals affected with congenital myopathy (PMID: 22473935, 23394784). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant malignant hyperthermia susceptibility conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.