Submissions for variant NM_000540.3(RYR1):c.13949T>C (p.Leu4650Pro)

dbSNP: rs118192138

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004992002	SCV005619837	uncertain significance	RYR1-related myopathy	2024-08-27	reviewed by expert panel	curation	The c.13949T>C variant in RYR1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 4650 (p.Leu4650Pro). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool gives a score of 0.805, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been detected in two individuals with central core disease (CCD). Of those individuals, both were compound heterozygous for the variant and a VUS and both of those were confirmed in trans by parental testing (RYR1 p.Lys4724Gln, PMID: 12937085, PMID: 30611313, ClinVar Variation ID: 65957) (PM3). At least one patient with this variant displayed Type I fiber predominance, unique large eccentric cores, few necrotic/regenerative fibers, and connective tissue increase, which is highly specific for RYR1-related myopathy (PP4, PMID: 12937085). In summary, the variant meets the criteria to be classified as uncertain significance for autosomal recessive RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3, PM3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119493	SCV000886062	likely pathogenic	not provided	2018-04-06	criteria provided, single submitter	clinical testing	The p.Leu4650Pro variant has been previously reported in an affected child who also carried p.Lys4724Gln variant on the other allele (Romero 2003). She was born at 37 weeks of gestation with prenatal history of hydramnion, fetal akinesia and breach presentation. She presented with multiple arthrogryposis, severe hypotonia, amyotrophy and hypomimia, and required respiratory mechanical assistance. Muscle biopsy at two months of age showed type I fiber predominance, unique large eccentric cores, some necrotic or regenerative fibers and connective tissue increase. At age 5, she was reported to have delayed motor development, ptosis and strabismus (Romero 2003). The p.Leu4650Pro variant is listed in ClinVar (Variation ID 65961). Additionally, in vitro functional studies with p.Phe1528Leu demonstrated that this variant results in excitation-contraction uncoupling by reducing channel opening in the absence of a change in calcium ion permeation (Dulhunty et al.)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039994	SCV001203546	likely pathogenic	RYR1-related disorder	2023-06-03	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (http://aups.org.au/Proceedings/43/186P/). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4650 of the RYR1 protein (p.Leu4650Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal recessive congenital myopathy (PMID: 12937085; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 65961). 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.
GeneReviews	RCV000056208	SCV000087297	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
RYR1 database	RCV000119493	SCV000154400	not provided	not provided		no assertion provided	not provided