Submissions for variant NM_000540.3(RYR1):c.9772G>A (p.Glu3258Lys)

gnomAD frequency: 0.00006  dbSNP: rs754431075

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688302	SCV000815907	uncertain significance	RYR1-related disorder	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3258 of the RYR1 protein (p.Glu3258Lys). This variant is present in population databases (rs754431075, gnomAD 0.04%). 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: 568062). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV001549837	SCV001770065	uncertain significance	not provided	2019-12-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Molecular Genetics, Royal Melbourne Hospital	RCV002221249	SCV002498659	uncertain significance	RYR1-related myopathy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace glutamic acid with lysine at codon 3258, p.(Glu3258Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in exon 66 outside of the C-terminal region, amino acids 4631-4991, that is defined as a mutational hotspot. There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in gnomAD v2.1 is 0.03% (12/3,4584 alleles, 0 homozygotes) in the Latino/admixed American population. The variant has been reported as a variant of uncertain significance (ClinVar ID: 568062), and to our knowledge, has not been reported in the literature in any individuals with RYR1-related disorders. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Fulgent Genetics, Fulgent Genetics	RCV002477538	SCV002775423	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	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001549837	SCV004236631	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002221249	SCV005399229	uncertain significance	RYR1-related myopathy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (PMID: 27855725, PMID: 23919265). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (19 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change, p.(Glu3258Gln), has been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar), and observed in a neuropathy study (PMID: 24627108). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign