ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13952A>C (p.His4651Pro)

dbSNP: rs118192139
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV000056198 SCV002073308 pathogenic Central core myopathy criteria provided, single submitter clinical testing The missense variant p.H4651P in RYR1 (NM_000540.3) has been previously reported in one patient in heterozygous state. The father of the patient was detected to be somatic mosaic for the same variant ( Davis MR et al). The variant is present in the hot-spot region for central core disease. It has been submitted to ClinVar as Pathogenic. The p.H4651P variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.H4651P missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 4651 of RYR1 is conserved in all mammalian species. The nucleotide c.13952 in RYR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003591653 SCV004297346 uncertain significance RYR1-related disorder 2024-04-08 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 4651 of the RYR1 protein (p.His4651Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with central core disease (PMID: 12565913). ClinVar contains an entry for this variant (Variation ID: 65951). 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 with a positive predictive value of 95%. This variant disrupts the p.His4651 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 12565913, 35428369), which suggests that this may be a clinically significant amino acid residue. 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.
GeneReviews RCV000056198 SCV000087287 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119494 SCV000154401 not provided not provided no assertion provided not provided

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