ClinVar Miner

Submissions for variant NM_001079802.2(FKTN):c.1261_1286delinsACC (p.Ala421fs)

dbSNP: rs1588315166
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000810998 SCV000951241 pathogenic Walker-Warburg congenital muscular dystrophy 2022-10-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala421Thrfs*25) in the FKTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the FKTN protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 558217). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the FKTN protein in which other variant(s) (p.Asp455Metfs*12) have been determined to be pathogenic (PMID: 17044012). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002440750 SCV002680219 likely pathogenic Cardiovascular phenotype 2019-12-06 criteria provided, single submitter clinical testing The c.1261_1286del26insACC variant, located in coding exon 9 of the FKTN gene, results from the deletion of 26 nucleotides and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.A421Tfs*25). This amino acid position is highly conserved in available vertebrate species. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of FKTN, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 41 amino acids of the protein. While the exact functional impact of these altered amino acids is unknown at this time, a likely pathogenic truncating alteration, p.D455Mfs*12, located downstream of this variant was detected in trans with the FKTN p.F390IFS*14 mutation in an individual with limb girdle muscular dystrophy (Godfrey C et al. Ann. Neurol., 2006 Nov;60:603-10). In addition, a missense alteration, p.N442S, was detected in an individual with limb girdle muscular dystrophy who also carried FKTN p.S299R (Smogavec M et al. Neurol Genet, 2017 Aug;3:e167). Together, these data suggest the C-terminus of FKTN is critical, and therefore, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002487764 SCV002782346 uncertain significance Dilated cardiomyopathy 1X; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4; Autosomal recessive limb-girdle muscular dystrophy type 2M; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4 2021-09-10 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003413631 SCV004106945 likely pathogenic FKTN-related condition 2023-06-27 criteria provided, single submitter clinical testing The FKTN c.1261_1286delinsACC variant is predicted to result in a frameshift and premature protein termination (p.Ala421Thrfs*25). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in FKTN are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003472410 SCV004199738 likely pathogenic Dilated cardiomyopathy 1X 2023-06-17 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.