ClinVar Genomic variation as it relates to human health

Variant summary: FKTN c.919C>T (p.Arg307X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.1106delT (p.Phe369fsX37) and c.1167dupA (p.Phe390fsX14)). The variant allele was found at a frequency of 2e-05 in 244338 control chromosomes (gnomAD). c.919C>T has been reported in the literature in individuals affected with Walker-Warburg Syndrome, Fukuyama-type congenital muscular dystrophy, and unexplained limb-girdle muscle weakness (Godfrey_2007, Yoshioka_2008, Johnson_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R307* pathogenic mutation (also known as c.919C>T), located in coding exon 7 of the FKTN gene, results from a C to T substitution at nucleotide position 919. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation was first reported in a homozygous Turkish case with severe neonatal onset Walker-Warburg syndrome (Godfrey C et al. Brain, 2007 Oct;130:2725-35). This mutation has also been detected in a compound heterozygous Fukuyama-type congenital muscular dystrophy case and a compound heterozygous limb girdle muscular dystrophy case with confirmed α-DG deficiency (Yoshioka M et al. Brain Dev., 2008 Jan;30:59-67; Johnson K et al. Skelet Muscle, 2018 07;8:23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 20961758, 34426522, 35843586, 30060766, 32528171, 33051673, 17878207, 17597323)

This sequence change creates a premature translational stop signal (p.Arg307*) in the FKTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKTN are known to be pathogenic (PMID: 17044012, 17878207, 18752264). This variant is present in population databases (rs267606814, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Fukuyama-type congenital muscular dystrophy and/or Walker-Warburg syndrome (PMID: 17597323, 17878207). ClinVar contains an entry for this variant (Variation ID: 3216). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MIM# 253800), muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 4 (MIM# 613152), and muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 (MIM# 611588). The association to cardiomyopathy, dilated, 1X (MIM# 611615) is not established (PanelApp). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with Walker-Warburg Syndrome, Fukuyama-type congenital muscular dystrophy, and limb-girdle muscular dystrophy (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign