ClinVar Genomic variation as it relates to human health

Variant summary: FKTN c.1112A>G (p.Tyr371Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251166 control chromosomes. c.1112A>G has been reported in the literature as a compound heterozygous genotype in two patients (two sisters) presenting with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI (Vuillaumier-Barrot_2009), as a compound heterozygous genotype in a patient with Fukuyama-type congenital muscular dystrophy (FCMD) (Kobayashi_2001, Tachikawa_2012) and as a complex genotype with reportedly pathogenic variants in three different genes to include this one, RBM20 and HCN4 in an individual with noncompaction cardiomyopathy (NCCM) (van Waning_2018). At least one publication reports experimental evidence evaluating an impact on protein function reporting that the mutant accumulated in the ER instead of Golgi (WT) (Tachikawa_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Lp/P, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 371 of the FKTN protein (p.Tyr371Cys). This variant is present in population databases (rs119464998, gnomAD 0.01%). This missense change has been observed in individuals with congenital muscular dystrophy (PMID: 11165248, 19179078; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKTN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FKTN function (PMID: 17034757, 22275357). For these reasons, this variant has been classified as Pathogenic.

The p.Y371C variant (also known as c.1112A>G), located in coding exon 8 of the FKTN gene, results from an A to G substitution at nucleotide position 1112. This alteration has been reported in subjects with features of Fukuyama-type congenital muscular dystrophy (FCMD) and in a noncompaction cardiomyopathy cohort (Kobayashi K et al. FEBS Lett, 2001 Feb;489:192-6; Vuillaumier-Barrot S et al. Neuromuscul Disord, 2009 Mar;19:182-8; van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722). Studies suggest this alteration may have an impact on protein function, however the exact function of fukutin is yet unknown (Xiong H et al. Biochem Biophys Res Commun, 2006 Dec;350:935-41; Tachikawa M et al. J Biol Chem, 2012 Mar;287:8398-406). The tyrosine at codon 371 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.