Submissions for variant NM_000540.3(RYR1):c.10648C>T (p.Arg3550Trp)

gnomAD frequency: 0.00008  dbSNP: rs536304635

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000656969	SCV000332275	uncertain significance	not provided	2015-06-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000338681	SCV000412748	likely benign	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 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.
Illumina Laboratory Services, Illumina	RCV000398390	SCV000412749	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000280179	SCV000412750	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.
Illumina Laboratory Services, Illumina	RCV000335257	SCV000412751	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000656969	SCV000565506	uncertain significance	not provided	2024-07-25	criteria provided, single submitter	clinical testing	Reported in an individual with myopathy, who also harbored a second RYR1 frameshift pathogenic variant; his affected son was found to only harbor the frameshift variant, thus indicating that R3550W did not segregate with the phenotype in the family (PMID: 29178655); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis 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.; This variant is associated with the following publications: (PMID: 31321302, 29178655, 31135626, 36417990)
PreventionGenetics, part of Exact Sciences	RCV000656969	SCV000852220	uncertain significance	not provided	2016-05-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818112	SCV000958709	pathogenic	RYR1-related disorder	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3550 of the RYR1 protein (p.Arg3550Trp). This variant is present in population databases (rs536304635, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 29178655, 31135626). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 281479). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266921	SCV001445102	uncertain significance	Inborn genetic diseases	2018-01-17	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731554	SCV001984026	likely benign	not specified	2020-09-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656969	SCV003820570	uncertain significance	not provided	2021-12-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000398390	SCV004847307	uncertain significance	Central core myopathy	2023-08-07	criteria provided, single submitter	clinical testing	The p.Arg3550Trp variant in RYR1 has been reported as compound heterozyguos with a pathogenic/likely pathogenic variant in at least two individuals with myopathy (Laughlin 2017 PMID: 29178655; Peddareddygari 2019 PMID: 31135626). It segreagated with disease in one family, but in a second family was not detected in a son of an affected proband who had some features of myopathy. It has also been identified in 0.15% (7/4824) of South Asian chromosomes and 0.013% (2/15276) of Latine/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 281479). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP1, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000656969	SCV005041999	likely pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	RYR1: PM3:Strong, PM2:Supporting, PP3