ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.9703A>C (p.Ser3235Arg)

gnomAD frequency: 0.00001  dbSNP: rs747488155
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519263 SCV000618901 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The S3235R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S3235R variant is observed in 1/16502 (0.01%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S3235R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000795671 SCV000935141 uncertain significance RYR1-related disorder 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 3235 of the RYR1 protein (p.Ser3235Arg). This variant is present in population databases (rs747488155, gnomAD 0.003%). 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: 450330). 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262656 SCV001440602 uncertain significance Malignant hyperthermia, susceptibility to, 1 2019-01-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002289709 SCV002580764 uncertain significance Central core myopathy 2022-03-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV002525168 SCV003576691 uncertain significance Inborn genetic diseases 2021-09-27 criteria provided, single submitter clinical testing The c.9703A>C (p.S3235R) alteration is located in exon 66 (coding exon 66) of the RYR1 gene. This alteration results from a A to C substitution at nucleotide position 9703, causing the serine (S) at amino acid position 3235 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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