Submissions for variant NM_000540.3(RYR1):c.13069C>A (p.Leu4357Met)

gnomAD frequency: 0.00003  dbSNP: rs1236057233

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655589	SCV000777520	uncertain significance	RYR1-related disorder	2022-07-11	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 544446). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4357 of the RYR1 protein (p.Leu4357Met).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702261	SCV005203389	uncertain significance	not specified	2024-07-19	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13069C>A (p.Leu4357Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 77144 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.13069C>A in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 544446). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV003330873	SCV004037525	not provided	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital myopathy with fiber type disproportion; Multiminicore myopathy		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 09-09-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.