Submissions for variant NM_000540.3(RYR1):c.4481T>C (p.Val1494Ala)

dbSNP: rs767928113

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000369799	SCV000412173	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270553	SCV000412174	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000306888	SCV000412175	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000364887	SCV000412176	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000369799	SCV000920384	likely pathogenic	Central core myopathy	2019-01-01	criteria provided, single submitter	research	The same individual also harbours another variant g.[38979895_38979897delGAG] in the same gene along with this variant as compound heterozygote
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224473	SCV001396667	uncertain significance	RYR1-related disorder	2022-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1494 of the RYR1 protein (p.Val1494Ala). This variant is present in population databases (rs767928113, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 31742715). ClinVar contains an entry for this variant (Variation ID: 329029). 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.
All of Us Research Program, National Institutes of Health	RCV000364887	SCV004833270	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782358	SCV005395616	uncertain significance	not specified	2024-09-06	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.4481T>C (p.Val1494Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.8e-05 in 1613752 control chromosomes, predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Congenital Multicore Myopathy With External Ophthalmoplegia, allowing no conclusion about variant significance. c.4481T>C has been reported in the literature in the compound heterozygous state together with a VUS in a fetus with multiple joint contractures and bilateral clubfoot who was suspected of central core disease (Aggarwal_2020, Saini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Multicore Myopathy With External Ophthalmoplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31742715, 35587316). ClinVar contains an entry for this variant (Variation ID: 329029). Based on the evidence outlined above, the variant was classified as uncertain significance.