Submissions for variant NM_000540.3(RYR1):c.13484C>T (p.Pro4495Leu)

gnomAD frequency: 0.00001  dbSNP: rs138929547

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721318	SCV000852349	uncertain significance	not provided	2015-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV001041642	SCV001205266	uncertain significance	RYR1-related disorder	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4495 of the RYR1 protein (p.Pro4495Leu). This variant is present in population databases (rs138929547, gnomAD 0.006%). This missense change has been observed in individual(s) with statin-induced myopathy (PMID: 30325262). ClinVar contains an entry for this variant (Variation ID: 590432). 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. 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.
GeneDx	RCV000721318	SCV001990436	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Classified as likely benign and detected by whole exome sequencing in a patient with severe statin-associated muscle symptom (Isackson et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30325262, 31851124)
Fulgent Genetics, Fulgent Genetics	RCV002485818	SCV002776017	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-11-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721318	SCV003810551	uncertain significance	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003994098	SCV004812383	uncertain significance	RYR1-related myopathy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace proline with leucine at codon 4495, p.(Pro4495Leu). The proline residue is located in an unconserved region (100 vertebrates, UCSC) in exon 92. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in gnomAD v2.1 is 0.006% (6/104,276 alleles) in the European (non-Finnish) population. This variant has been reported in at least one individual with severe statin-associated muscle symptoms (PMID: 30325262, 31851124 ). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
All of Us Research Program, National Institutes of Health	RCV003999818	SCV004816236	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 4495 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 not been reported in individuals affected with malignant hyperthermia susceptibility, although it has been reported in an individual affected with statin-associated muscle symptoms (PMID: 30325262). This variant has been identified in 6/232162 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.