ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.2996G>A (p.Arg999His) (rs180714609)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119605 SCV000345535 uncertain significance not provided 2016-09-15 criteria provided, single submitter clinical testing
GeneDx RCV000119605 SCV000620280 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing The R999H variant in the RYR1 gene has been reported previously in the heterozygous state in a patient with multi-minicore disease; this variant was also present in a mildly affected sibling and her unaffected mother (Ducreux et al., 2006). The R999H variant is observed in 2/11344 (0.017%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The R999H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In vitro analysis of R999H indicates that this variant does not affect the intracellular Ca2+ release or sensitivity of the receptor to 4-cmc (Ducreux et al., 2006). We interpret R999H as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000310667 SCV000412003 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346959 SCV000412004 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000391226 SCV000412005 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000307345 SCV000412006 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000822159 SCV000962949 uncertain significance RYR1-Related Disorders 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 999 of the RYR1 protein (p.Arg999His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs180714609, ExAC 0.02%). This variant has been observed in in the heterozygous state in two individuals affected with multiminicore disease and in an unaffected parent (PMID: 16372898). ClinVar contains an entry for this variant (Variation ID: 133122). Experimental studies have shown that this missense change results in a calcium channel that behaves similar to wild-type (PMID: 16372898). 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.
Leiden Muscular Dystrophy (RYR1) RCV000119605 SCV000154512 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119605 SCV000852556 uncertain significance not provided 2013-10-21 criteria provided, single submitter clinical testing

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