ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.4934G>T (p.Arg1645Leu) (rs193922778)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554995 SCV000659950 likely pathogenic RYR1-Related Disorders 2019-04-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1645 of the RYR1 protein (p.Arg1645Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant also falls at the last nucleotide of exon 33 of the RYR1 coding sequence, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital myopathy (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. A different variant affecting this nucleotide (c.4934G>A) has been reported to cause a splicing defect in an individual affected with autosomal recessive congenital myopathy (PMID: 18253926). This suggests that this nucleotide may be important for normal RNA splicing. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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