ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1100T>C (p.Ile367Thr) (rs1555739020)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527187 SCV000630828 uncertain significance Walker-Warburg congenital muscular dystrophy 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 367 of the FKRP protein (p.Ile367Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with a dystrophinopathy (PMID: 28112097). In addition, this variant occurs with a pathogenic variant (p.Arg48Valfs*20) in FKRP in an individual with congenital muscular dystrophy 1C (Invitae). Family studies indicate these two variants are on opposite chromosomes (in trans), which suggests the c.1100T>C substitution may contribute to disease. 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"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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