ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10280C>T (p.Pro3427Leu)

gnomAD frequency: 0.00006  dbSNP: rs775773632
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000821198 SCV000961947 uncertain significance RYR1-related disorder 2022-09-02 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 3427 of the RYR1 protein (p.Pro3427Leu). This variant is present in population databases (rs775773632, gnomAD 0.01%). 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: 663339). 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 RCV002487838 SCV002777365 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 2021-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV002537496 SCV003746065 uncertain significance Inborn genetic diseases 2022-12-27 criteria provided, single submitter clinical testing The c.10280C>T (p.P3427L) alteration is located in exon 68 (coding exon 68) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 10280, causing the proline (P) at amino acid position 3427 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV003132104 SCV003812484 uncertain significance not provided 2022-07-26 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002831 SCV004819829 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-08-25 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 3427 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 6/268138 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.

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