ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.8078C>T (p.Pro2693Leu)

gnomAD frequency: 0.00001  dbSNP: rs568662364
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001093151 SCV001249995 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002482166 SCV002777132 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 2021-07-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV004031995 SCV004943169 uncertain significance Inborn genetic diseases 2024-01-04 criteria provided, single submitter clinical testing The c.8078C>T (p.P2693L) alteration is located in exon 51 (coding exon 51) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 8078, causing the proline (P) at amino acid position 2693 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV005093466 SCV005823241 uncertain significance RYR1-related disorder 2024-02-20 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 2693 of the RYR1 protein (p.Pro2693Leu). This variant is present in population databases (rs568662364, gnomAD 0.02%). 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: 872587). 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 with a negative predictive value of 95%. 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.

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