Submissions for variant NM_000540.3(RYR1):c.2216C>T (p.Pro739Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
All of Us Research Program, National Institutes of Health	RCV004009971	SCV004818593	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 739 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 RYR1-related disorders in the literature. This variant has been identified in 1/251380 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.
Ambry Genetics	RCV004371942	SCV004945824	uncertain significance	Inborn genetic diseases	2023-11-28	criteria provided, single submitter	clinical testing	The c.2216C>T (p.P739L) alteration is located in exon 19 (coding exon 19) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 2216, causing the proline (P) at amino acid position 739 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103218	SCV005767384	uncertain significance	RYR1-related disorder	2024-10-23	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 739 of the RYR1 protein (p.Pro739Leu). This variant is present in population databases (rs760127779, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 95%. 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.