Submissions for variant NM_000540.3(RYR1):c.10219G>A (p.Ala3407Thr)

gnomAD frequency: 0.00006  dbSNP: rs143533100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513119	SCV000569485	uncertain significance	not provided	2024-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported with a second RYR1 variant on the opposite allele (in trans) in a patient with rhabdomyolysis in the published literature, but it is unknown whether this individual was tested for variants in other genes associated with rhabdomyolysis (PMID: 25960145); This variant is associated with the following publications: (PMID: 25960145, 32978841, 30788618)
CeGaT Center for Human Genetics Tuebingen	RCV000513119	SCV000608902	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV001851191	SCV002293892	uncertain significance	RYR1-related disorder	2021-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3407 of the RYR1 protein (p.Ala3407Thr). This variant is present in population databases (rs143533100, gnomAD 0.007%). This missense change has been observed in individual(s) with exercise-induced rhabdomyolisis (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 420587). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002481517	SCV002781765	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	2021-10-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001851191	SCV004708995	uncertain significance	RYR1-related disorder	2023-10-28	criteria provided, single submitter	clinical testing	The RYR1 c.10219G>A variant is predicted to result in the amino acid substitution p.Ala3407Thr. This variant has been reported in an individual with RYR1-related myopathies, along with another missense variant (patient 52 in Table 3, Snoeck et al. 2015. PubMed ID: 25960145). An alternate nucleotide change affecting the same amino acid (c.10219G>T; p.Ala3407Ser) has also been reported in individuals with rhabdomyolysis (Molenaar et al. 2014. PubMed ID: 25081049; patient 29 in Table 3, Snoeck et al. 2015. PubMed ID: 25960145). The c.10219G>A (p.Ala3407Thr) variant is reported in 0.0069% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39010054-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003329	SCV004820976	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 3407 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotypes (PMID: 25960145, 30788618). This variant has been identified in 9/259766 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.
GenomeConnect, ClinGen	RCV001851191	SCV000607369	not provided	RYR1-related disorder		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.