ClinVar Miner

Submissions for variant NM_001079802.2(FKTN):c.642dup (p.Asp215Ter) (rs398123557)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169031 SCV000220181 likely pathogenic Fukuyama congenital muscular dystrophy 2014-03-22 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079438 SCV000281461 pathogenic not provided 2015-01-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079438 SCV000331086 pathogenic not provided 2012-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000079438 SCV000491171 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing The c.642dupT pathogenic variant in the FKTN gene has been reported in a homozygous state in one individual with Walker-Warburg syndrome (WWS), an alpha-dystroglycanopathy that affects development of the brain, eyes, and muscle (Manzini et al., 2012). The c.642dupT variant causes a duplication of the Thymidine nucleotide at position 642, which results in a premature stop codon at protein residue 215 and is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the FKTN gene have been reported in HGMD in association with alpha-dystroglycanopathies (Stenson et al., 2014). Furthermore, the c.642dupT pathogenic variant was not observed in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.642dupT in the FKTN gene is interpreted as a pathogenic variant. As alpha-dystroglycanopathy due to pathogenic variants in the FKTN gene is an autosomal recessive disease, it is expected that an affected individual would harbor variants in both alleles of the FKTN gene (in trans). No second pathogenic variant was identified by this sequencing or deletion/duplication analysis analysis. The possibility that this patient harbors a second pathogenic FKTN variant that is undetectable by this test cannot be excluded.
Invitae RCV000472307 SCV000546097 pathogenic Walker-Warburg congenital muscular dystrophy 2019-11-12 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 6 of the FKTN mRNA (c.642dupT), causing a frameshift at codon 215. This creates a premature translational stop signal (p.Asp215*) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKTN are known to be pathogenic (PMID: 17878207). This particular variant has been observed in the homozygous state in an individual with Walker-Warburg syndrome (PMID: 22958903). ClinVar contains an entry for this variant (Variation ID: 93523). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000079438 SCV000885466 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing The FKTN c.642dupT; p.Asp215Ter variant has been reported in the homozygous state in an individual diagnosed with Walker-Warburg Syndrome (Manzini 2012). This variant causes a frameshift by inserting a single nucleotide, resulting in a premature termination codon in exon 6, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.01% (identified on 34 out of 245,138 chromosomes), and is classified as pathogenic/likely pathogenic in ClinVar (variant ID 93523). Based on the available information, this variant is considered pathogenic.

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