ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1250T>C (p.Leu417Pro) (rs764262446)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000655525 SCV000777456 likely pathogenic RYR1-Related Disorders 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 417 of the RYR1 protein (p.Leu417Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs764262446, ExAC 0.2%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with congenital myopathy (PMID: 22473935). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 544398). 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"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658830 SCV000780626 likely pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing

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