ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.1442C>A (p.Pro481His) (rs727502844)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000724960 SCV000196822 uncertain significance not provided 2014-02-27 criteria provided, single submitter clinical testing p.Pro481His (CCC>CAC): c.1442 C>A in exon 4 of the FKRP gene (NM_024301.4). The P481H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P481H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species within the lumenal domain of the protein and missense mutations in nearby residues (F473C, I478T, L489R) have been reported in association with Walker-Warburg syndrome. However, in silico analysis predicts this variant to have a benign effect on the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CORTICAL-BRAIN panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724960 SCV000332759 uncertain significance not provided 2015-07-14 criteria provided, single submitter clinical testing
Invitae RCV000684981 SCV000812449 uncertain significance Walker-Warburg congenital muscular dystrophy 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 481 of the FKRP protein (p.Pro481His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 162562). 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, 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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