Submissions for variant NM_000540.3(RYR1):c.4038C>A (p.Asn1346Lys)

gnomAD frequency: 0.00006  dbSNP: rs777049924

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657029	SCV000344618	uncertain significance	not provided	2016-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000313458	SCV000412092	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000370505	SCV000412093	uncertain significance	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000273611	SCV000412094	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-01-13	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	RCV000331017	SCV000412095	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-13	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.
GeneDx	RCV000657029	SCV000589419	likely benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29382405)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655552	SCV000777483	uncertain significance	RYR1-related disorder	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1346 of the RYR1 protein (p.Asn1346Lys). This variant is present in population databases (rs777049924, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 290117). 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 not expected to disrupt 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.
PreventionGenetics, part of Exact Sciences	RCV000657029	SCV000852596	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657029	SCV003813150	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000273611	SCV004820825	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1346 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital myopathy, who carried a different pathogenic variant in the same gene (PMID: 29382405). This variant has not been reported in an individual with malignant hyperthermia susceptibility in the literature. This variant has been identified in 17/185820 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657029	SCV005408807	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	BP2