ClinVar Miner

Submissions for variant NM_006731.2(FKTN):c.1167dup (p.Phe390fs) (rs398123555)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411292 SCV000485175 pathogenic Fukuyama congenital muscular dystrophy 2016-03-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079427 SCV000331176 pathogenic not provided 2012-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000079427 SCV000329807 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing The c.1167dupA pathogenic variant in the FKTN gene has been reported previously in association with Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy (LGMD), and Walker-Warburg syndrome (WWS) (Kondo-Iida et al., 1999; Godfrey et al., 2006; Contarelo et al., 2008; Manzini et al., 2008; Chang et al., 2009). Initially, Kondo-Iida et al. (1999) reported c.1167dupA occured de novo in a Japanese individual with FCMD, who also harbored the common 3kb retrotransposal insertion in the FKTN gene which was maternally inherited. Subsequently, Godfrey et al. (2006) reported c.1167dupA in three individuals with LGMD who all harbored an additional pathogenic variant in the FKTN gene in trans. In addition, c.1167dupA has been reported to be homozygous in several unrelated individuals of Ashkenazi Jewish ancestry who have WWS, and has been identified in heterozygosity in 2/299 (0.7%) healthy American Ashkenazi Jewish adults, suggesting this may be founder mutation in this population (Contarelo et al., 2008; Manzini et al., 2008; Chang et al., 2009). Similarly, the c.1167dupA variant was observed in 77/9,834 (0.8%) alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016). The c.1167dupA variant causes a shift in reading frame starting at codon phenylalanine 390, changing it to an isoleucine, and creates a premature stop codon at position 14 of the new reading frame, denoted p.Phe390IlefsX14. This frameshift variant in the C-terminus is predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 13 incorrect amino acids. Furthermore, other downstream frameshift variants in the FKTN gene have been reported in the Human Gene Mutation Database in association with alpha-dystroglycanopathies (Stenson et al., 2014).
Illumina Clinical Services Laboratory,Illumina RCV000778871 SCV000915268 pathogenic FKTN-Related Disorders 2018-11-13 criteria provided, single submitter clinical testing The FKTN c.1167dupA (p.Phe390IlefsTer14) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the literature, the p.Phe390IlefsTer14 variant has been reported in at least 13 individuals, four of whom are related, diagnosed with a range of conditions. The p.Phe390IlefsTer14 variant was reported to occur de novo in a Japanese individual with a severe Fukuyama congenital muscular dystrophy (FCMD), who also carried the common 3 kb retrotransposal insertion allele in the FKTN gene (Kondo-lida et al. 1999). The variant has also been reported also reported in a compound heterozygous state in three individuals presenting with a limb girdle muscular dystrophy with no intellectual disability or brain abnormalities; two of the individuals are related and carry the variant in trans with a missense variant while the third carried the variant in trans with a second frameshift variant (Godfrey et al. 2006). Additionally the p.Phe390IlefsTer14 variant has been reported in a homozygous state in nine individuals with Walker-Warburg syndrome, a more severe phenotype, all of whom are of Ashkenazi Jewish ancestry from non-consanguineous families and share a common haplotype. The variant was detected in two or 299 alleles in a healthy American Ashkenazi Jewish control population suggesting this may be a founder variant in this population (Cotarelo et al. 2008; Manzini et al. 2008; Chang et al. 2009). The p.Phe390IlefsTer14 variant is reported at a frequency of 0.007991 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Phe390IlefsTer14 variant is classified as pathogenic for FKTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000411292 SCV000698716 pathogenic Fukuyama congenital muscular dystrophy 2016-01-18 criteria provided, single submitter clinical testing
Invitae RCV000634081 SCV000755359 pathogenic Walker-Warburg congenital muscular dystrophy 2019-01-07 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FKTN gene (p.Phe390Ilefs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acids of the FKTN protein. This variant is present in population databases (rs756763804, ExAC 0.05%). This variant has been reported as homozygous or in combination with other variants in the FKTN gene in several individuals affected with dystroglycanopathies and has been shown to segregate with the disease in one family (PMID: 17878207, 18177472, 18752264 , 19266496, 27065010). ClinVar contains an entry for this variant (Variation ID: 3203). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003356 SCV000023514 pathogenic Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A4 2008-02-01 no assertion criteria provided literature only
OMIM RCV000003357 SCV000023515 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C4 2008-02-01 no assertion criteria provided literature only

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