ClinVar Miner

Submissions for variant NM_024301.5(FKRP):c.37G>A (p.Ala13Thr) (rs768376273)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543616 SCV000630838 uncertain significance Walker-Warburg congenital muscular dystrophy 2017-03-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 13 of the FKRP protein (p.Ala13Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs768376273, ExAC 0.01%) but 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786132 SCV000924794 uncertain significance not provided 2017-05-02 no assertion criteria provided provider interpretation Our patient had testing at the Invitae laboratory. Given the lack of case data, the fact that this is a heterozygous variant in a gene associated with autosomal recessive disease, and overall lack of gene-phenotype association, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The FKRP gene is associated with autosomal recessive muscular dystrophy and DCM. Our patient has only one heterozygous variant, and a phenotype of Afib. The variant has not been reported in any cases of FKRP-related disease. The variant is present in 1 individual listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was observed in 1 of 16,627 individuals of Latino descent (MAF = 0.003%). The average coverage at that site in gnomAD is 30x. It should be noted that this variant is filtered out due to quality filters on first pass.

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