Submissions for variant NM_000540.3(RYR1):c.3304G>A (p.Gly1102Ser)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002611639	SCV003504680	uncertain significance	RYR1-related disorder	2022-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1102 of the RYR1 protein (p.Gly1102Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. 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. 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.
Revvity Omics, Revvity	RCV003130848	SCV003814352	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004009476	SCV004830009	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1102 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 RYR1-related disorders in the literature. 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 disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004961116	SCV005496926	uncertain significance	Inborn genetic diseases	2024-10-29	criteria provided, single submitter	clinical testing	The c.3304G>A (p.G1102S) alteration is located in exon 25 (coding exon 25) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 3304, causing the glycine (G) at amino acid position 1102 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.