Submissions for variant NM_000540.3(RYR1):c.4237G>A (p.Asp1413Asn)

gnomAD frequency: 0.00016  dbSNP: rs139142846

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV001237263	SCV000852610	uncertain significance	RYR1-related disorder	2023-10-23	criteria provided, single submitter	clinical testing	The RYR1 c.4237G>A variant is predicted to result in the amino acid substitution p.Asp1413Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38966034-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae	RCV001237263	SCV001410017	uncertain significance	RYR1-related disorder	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1413 of the RYR1 protein (p.Asp1413Asn). This variant is present in population databases (rs139142846, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 590529). 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. 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	RCV002485824	SCV002785843	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	2021-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000721527	SCV003805779	uncertain significance	not provided	2022-08-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000721527	SCV003812459	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999843	SCV004815165	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1413 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RYR1-related disorders in the literature. This variant has been identified in 9/282154 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.