Submissions for variant NM_000540.3(RYR1):c.8888T>C (p.Leu2963Pro)

gnomAD frequency: 0.00001  dbSNP: rs756870293

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV002537021	SCV005367854	pathogenic	RYR1-related myopathy	2024-08-07	reviewed by expert panel	curation	The NM_000540.3:c.8888T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 2963 (p.Leu2963Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1179858 alleles) in the European (non-Finnish) population (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.841, which is above the threshold necessary to apply PP3. This variant has been reported in five probands with RYR1-related myopathy (PM3_VeryStrong). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.6721C>T(p.Arg2241Ter), c.14416A>G(p.Asn4806Asp), c.46-1G>A, ) and three of those were confirmed in trans (PMIDs:24951453, 27234031; SCV003761249.1; VCEP internal data). One individual was homozygous for the variant (PMIDs:23826317). The variant has been reported to segregate in one affected sibling from a family (PP1, PMID: 24951453). Western blot analysis of a deltoid muscle extract revealed a strong reduction of the RYR1 protein level by 37% in patient cells compared to a healthy age-matched control, supporting that the variant reduced protein expression (PS3_Supporting, PMID:23826317). In summary, the variant meets the criteria to be classified as Pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796219	SCV000935724	pathogenic	RYR1-related disorder	2024-02-17	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 2963 of the RYR1 protein (p.Leu2963Pro). This variant is present in population databases (rs756870293, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive RYR1-related myopathy (PMID: 23826317, 24951453, 27234031). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 642707). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23826317). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814236	SCV001755390	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784413	SCV002019942	pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002537021	SCV003761249	likely pathogenic	RYR1-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Leu2963Pro variant in RYR1 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 1524261), in one individual with centronuclear myopathy. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 1524261). The p.Leu2963Pro variant in RYR1 has been previously reported in three unrelated individuals with RYR1-related myopathy (PMID: 27234031, PMID: 24951453, PMID: 24951453), but has been identified in 2/113766 (0.001758%) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756870293). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these three affected individuals that were previously reported, one was a homozygote (PMID: 23826317), one who was a compound heterozygote who carried a reported likely pathogenic variant in trans (PMID: 24951453, ClinVar Variation ID: 159856), and one who was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 27234031, ClinVar Variation ID: 265505), which increases the likelihood that the p.Leu2963Pro variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 642707) and has been interpreted as pathogenic by Invitae, PerkinElmer Genomics, and Kariminejad - Najmabadi Pathology & Genetics Center. In vitro functional studies provide some evidence that the p.Leu2963Pro variant may slightly impact protein function (PMID: 23826317). However, these types of assays may not accurately represent biological function. 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, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PM2_Supporting, PP3 (Richards 2015).
Athena Diagnostics	RCV001784413	SCV004229928	likely pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple families with an autosomal recessive RYR1-related myopathy, including both congenital and adult-onset forms. Computational tools predict that this variant is damaging.
All of Us Research Program, National Institutes of Health	RCV004001599	SCV004834112	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 2963 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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: 642707). This variant has been identified in 2/251486 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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586930	SCV005038489	likely pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PM2+PM3_Supporting+PP2+PP3+PP4
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV004556822	SCV005045781	likely pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-08-17	criteria provided, single submitter	clinical testing	Likely path for myopathy.
GeneDx	RCV001784413	SCV005081554	likely pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state without a second RYR1 variant in a clinically asymptomatic individual with hyperCKemia in the published literature (PMID: 31517061); This variant is associated with the following publications: (PMID: 23826317, 25127990, 27234031, 34426522, 12668474, 37643885, 31517061, 24951453)