ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13949T>C (p.Leu4650Pro) (rs118192138)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000119493 SCV000886062 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing The p.Leu4650Pro variant has been previously reported in an affected child who also carried p.Lys4724Gln variant on the other allele (Romero 2003). She was born at 37 weeks of gestation with prenatal history of hydramnion, fetal akinesia and breach presentation. She presented with multiple arthrogryposis, severe hypotonia, amyotrophy and hypomimia, and required respiratory mechanical assistance. Muscle biopsy at two months of age showed type I fiber predominance, unique large eccentric cores, some necrotic or regenerative fibers and connective tissue increase. At age 5, she was reported to have delayed motor development, ptosis and strabismus (Romero 2003). The p.Leu4650Pro variant is listed in ClinVar (Variation ID 65961). Additionally, in vitro functional studies with p.Phe1528Leu demonstrated that this variant results in excitation-contraction uncoupling by reducing channel opening in the absence of a change in calcium ion permeation (Dulhunty et al.)
Invitae RCV001039994 SCV001203546 uncertain significance RYR1-Related Disorders 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 4650 of the RYR1 protein (p.Leu4650Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 12937085). ClinVar contains an entry for this variant (Variation ID: 65961). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). 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.
GeneReviews RCV000056208 SCV000087297 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119493 SCV000154400 not provided not provided no assertion provided not provided

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