ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.52C>T (p.Leu18Phe) (rs1226848053)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658156 SCV000779927 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FKRP gene. The L18F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L18F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the L18F variant is not observed in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001050758 SCV001214880 uncertain significance Walker-Warburg congenital muscular dystrophy 2019-03-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 18 of the FKRP protein (p.Leu18Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 546302). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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