Submissions for variant NM_000540.3(RYR1):c.6707T>G (p.Leu2236Arg)

dbSNP: rs1969830618

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322993	SCV001513890	likely pathogenic	RYR1-related disorder	2024-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2236 of the RYR1 protein (p.Leu2236Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). 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: 1023007). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. 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.
Athena Diagnostics	RCV001664825	SCV001880063	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002543847	SCV003603989	uncertain significance	Inborn genetic diseases	2022-01-04	criteria provided, single submitter	clinical testing	The c.6707T>G (p.L2236R) alteration is located in exon 41 (coding exon 41) of the RYR1 gene. This alteration results from a T to G substitution at nucleotide position 6707, causing the leucine (L) at amino acid position 2236 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782708	SCV005394193	uncertain significance	not specified	2024-09-27	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6707T>G (p.Leu2236Arg) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251106 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.6707T>G in individuals affected with Congenital Multicore Myopathy With External Ophthalmoplegia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1023007). Based on the evidence outlined above, the variant was classified as uncertain significance.