ClinVar Miner

Submissions for variant NM_006731.2(FKTN):c.1337A>T (p.Asn446Ile) (rs374912618)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498728 SCV000589960 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FKTN gene. The N446I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N446I variant is observed in 40/16,510 (0.2%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N446I 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with alpha-dystroglycanopathies (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000634077 SCV000755355 uncertain significance Walker-Warburg congenital muscular dystrophy 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 446 of the FKTN protein (p.Asn446Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs374912618, ExAC 0.2%). This variant has not been reported in the literature in individuals with FKTN-related disease. ClinVar contains an entry for this variant (Variation ID: 432249). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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