ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2203C>T (p.His735Tyr)

gnomAD frequency: 0.00002  dbSNP: rs771629253
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001945856 SCV002200450 uncertain significance RYR1-related disorder 2022-09-13 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 735 of the RYR1 protein (p.His735Tyr). This variant is present in population databases (rs771629253, gnomAD 0.1%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 27066551). ClinVar contains an entry for this variant (Variation ID: 1427206). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282651 SCV002571801 likely benign not specified 2022-08-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001945856 SCV004765953 uncertain significance RYR1-related disorder 2023-12-13 criteria provided, single submitter clinical testing The RYR1 c.2203C>T variant is predicted to result in the amino acid substitution p.His735Tyr. This variant was reported in an individual who presented in infancy with congenital myopathy, but the variant was paternally inherited and no second RYR1 was detected (Tian et al 2015. PubMed ID: 27066551). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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