ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7850C>T (p.Ser2617Leu)

gnomAD frequency: 0.00001  dbSNP: rs780836747
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001910962 SCV002162013 uncertain significance RYR1-related disorder 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2617 of the RYR1 protein (p.Ser2617Leu). This variant is present in population databases (rs780836747, gnomAD 0.009%). 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: 1391300). 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.
Revvity Omics, Revvity RCV003134198 SCV003810524 uncertain significance not provided 2019-08-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV003355619 SCV004063041 uncertain significance Inborn genetic diseases 2023-09-12 criteria provided, single submitter clinical testing The c.7850C>T (p.S2617L) alteration is located in exon 49 (coding exon 49) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 7850, causing the serine (S) at amino acid position 2617 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004010781 SCV004820929 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-07-29 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 2617 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 RYR1-related disorders in the literature. This variant has been identified in 7/280910 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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