ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14818G>A (p.Ala4940Thr) (rs118192158)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119566 SCV000225118 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
GeneDx RCV000119566 SCV000329509 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing The A4940T pathogenic variant in the RYR1 gene has been reported previously in affected individuals from two families with central core disease, including a more mildly affected mother in one family with sequencing suggestive of somatic mosaicism (Davis et al., 2003; Kraeva et al., 2013). An additional publication reported A4940T in a patient with malignant hyperthermia susceptibility (Sambuughin et al., 2005). Transgenic C. elegans with the A4940T variant showed increased sensitivity to halothane and caffeine, with decreased locomotion (Baines et al., 2017). The A4940T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position in the C-terminal transmembrane region, which has been found to be a hotspot for variants related to central core disease (Davis et al., 2003). Therefore, we interpret A4940T as a pathogenic variant, and its presence is consistent with a diagnosis of a RYR1-related disorder in this individual.
GeneReviews RCV000056174 SCV000087262 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000119566 SCV000194811 pathogenic not provided 2013-03-27 criteria provided, single submitter clinical testing
Invitae RCV000529075 SCV000659859 pathogenic RYR1-Related Disorders 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 4940 of the RYR1 protein (p.Ala4940Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases at a very low frequency (rs118192158, ExAC <0.01%). This variant has been reported in several families affected with central core disease and in two individuals affected with susceptibility to malignant hyperthermia  (PMID: 1256913, 14670767,12467748, 15731587, 23558838). This variant has been reported to segregate with with disease in a family affected with autosomal dominant central core disease (PMID: 23183335). ClinVar contains an entry for this variant (Variation ID: 65927). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This missense change is located in the C-terminal region of the RYR1 protein where many other previously reported pathogenic mutations have been found (PMID: 16084090). For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119566 SCV000154473 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119566 SCV000852464 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing

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