Submissions for variant NM_000540.3(RYR1):c.1250T>C (p.Leu417Pro)

gnomAD frequency: 0.00004  dbSNP: rs764262446

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655525	SCV000777456	pathogenic	RYR1-related disorder	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 417 of the RYR1 protein (p.Leu417Pro). This variant is present in population databases (rs764262446, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 21911697, 22473935; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 544398). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000658830	SCV000780626	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729679	SCV001976810	likely pathogenic	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PM3, PP2, PP3
3billion, Medical Genetics	RCV002250674	SCV002521654	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000544398). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22473935). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000658830	SCV003814457	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003334390	SCV004042750	likely pathogenic	See cases	2023-02-13	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PP3_STR, PS4_MOD, PM2_SUP
All of Us Research Program, National Institutes of Health	RCV004004138	SCV004820741	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 417 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). This variant occurs in the N-terminal region (a.a. 1-552) of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 544398). This variant has been identified in 9/207268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525996	SCV005040007	likely pathogenic	Myopathy, RYR1-associated	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.1250T>C (p.Leu417Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 207268 control chromosomes. c.1250T>C has been reported in the literature in individuals affected with congenital myopathies and central core disease in the compound heterozygous state (Klein_2011, Herman_2021, Rossi_2021, Marinakis_2021, Fusto_2022). These data indicate that the variant is likely to be associated with disease. 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: 21911697, 33146414, 33758288, 34008892, 35428369). ClinVar contains an entry for this variant (Variation ID: 544398). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000658830	SCV005440758	likely pathogenic	not provided	2024-06-22	criteria provided, single submitter	clinical testing	Previously identified in patients tested at GeneDx and in the literature with RYR1-related myopathy who had a second RYR1 variant, however phase was not determined (PMID: 33642296); Previously reported in the heterozygous state in a patient with fetal akinesia and moderate myopathy (PMID: 35428369); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21911697, 33767344, 22473935, 33146414, 34008892, 33642296, 35428369, 37510394)
Fulgent Genetics, Fulgent Genetics	RCV005019091	SCV005647452	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-05-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000655525	SCV005351532	likely pathogenic	RYR1-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The RYR1 c.1250T>C variant is predicted to result in the amino acid substitution p.Leu417Pro. This variant was reported in the compound heterozygous state with another RYR1 loss of function variant in at least two individuals with RYR1-related myopathy (See patient 32 in Klein et al. 2011. PubMed ID: 21911697; See case ID 9166 in Supp. Table 2 Marinakis et al. 2021. PubMed ID: 34008892). This variant was also reported in an additional study as compound heterozygous in a patient with pediatric neuromuscular disease, but the second variant was not listed (See Supp. Table 2 in Herman et al. 2020. PubMed ID: 33146414). This variant was found in a patient in a cohort study of RYR1-related congenital myopathies, but no zygosity information was provided (Table 2 and Additional file 4,  Fusto. 2022. PubMed ID: 35428369).  This variant is reported in 0.027% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal recessive RYR1-related myopathy.