ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.511C>G (p.Leu171Val) (rs766747690)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432470 SCV000534913 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing The L171V variant of uncertain significance in the FKRP gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. L171V was not observed in approximately 5,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 4X), nor was it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. The L171V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. And while this substitution occurs at a position that is highly conserved across species, V171 is the native amino acid residue in at least one species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000475297 SCV000548522 uncertain significance Walker-Warburg congenital muscular dystrophy 2016-12-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 171 of the FKRP protein (p.Leu171Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. The frequency data for this variant (rs766747690) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a FKRP-related 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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