ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.9047A>G (p.Tyr3016Cys) (rs1555786853)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558544 SCV000660079 likely pathogenic RYR1-Related Disorders 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 3016 of the RYR1 protein (p.Tyr3016Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal recessive congenital myopathy in 5 affected individuals from one family (PMID: 23894444), and in 2 individuals from a second family affected with neuromuscular disease (Invitae database). Experimental studies in muscle biopsies from affected individuals have shown that this missense change leads to a reduction in RYR1 protein levels (PMID: 23894444). This variant disrupts the p.Tyr3016 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 27447704), which suggests that this may be a clinically significant amino acid residue. In summary, this variant has been reported to segregate with RYR1-related disorders in 2 families and is absent from the general population. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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