Submissions for variant NM_000540.3(RYR1):c.3877C>A (p.Pro1293Thr)

gnomAD frequency: 0.00002  dbSNP: rs146407179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001223356	SCV001395500	likely pathogenic	RYR1-related disorder	2023-09-08	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. 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. ClinVar contains an entry for this variant (Variation ID: 440962). This missense change has been observed in individual(s) with autosomal recessive multiminicore disease (PMID: 22473935). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs146407179, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1293 of the RYR1 protein (p.Pro1293Thr).
Revvity Omics, Revvity	RCV001703183	SCV003812405	uncertain significance	not provided	2020-03-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003564	SCV004831812	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1293 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 36283893), but may also be associated with other phenotype(s) (ClinVar Variation ID: 440962). This variant has been identified in 3/279980 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
GenomeConnect, ClinGen	RCV000509349	SCV000606969	not provided	Malignant hyperthermia, susceptibility to, 1; Congenital myopathy with fiber type disproportion; Multiminicore myopathy; Centronuclear myopathy		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001703183	SCV001929717	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001703183	SCV001954521	likely pathogenic	not provided		no assertion criteria provided	clinical testing