Submissions for variant NM_000540.3(RYR1):c.3299G>A (p.Arg1100His)

gnomAD frequency: 0.00001  dbSNP: rs755973279

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000355580	SCV000412027	uncertain significance	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000260823	SCV000412028	uncertain significance	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297339	SCV000412029	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000370749	SCV000412030	uncertain significance	Multiminicore myopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001753789	SCV001995921	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850757	SCV002171541	uncertain significance	RYR1-related disorder	2022-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1100 of the RYR1 protein (p.Arg1100His). This variant is present in population databases (rs755973279, 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: 329008). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002521219	SCV003634901	uncertain significance	Inborn genetic diseases	2022-06-24	criteria provided, single submitter	clinical testing	The c.3299G>A (p.R1100H) 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 3299, causing the arginine (R) at amino acid position 1100 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003995864	SCV004820807	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1100 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 in the literature. This variant has been identified in 4/251426 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.