ClinVar Miner

Submissions for variant NM_001079802.2(FKTN):c.557A>G (p.His186Arg)

dbSNP: rs1448279636
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670042 SCV000794853 uncertain significance Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 2017-10-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV004026112 SCV003559176 uncertain significance Cardiovascular phenotype 2024-09-13 criteria provided, single submitter clinical testing The p.H186R variant (also known as c.557A>G), located in coding exon 4 of the FKTN gene, results from an A to G substitution at nucleotide position 557. The histidine at codon 186 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as homozygous in an individual with Walker-Warburg syndrome (Manzini MC et al. Hum Mutat, 2008 Nov;29:E231-41). In multiple assays testing FKTN function, this variant showed functionally abnormal and functionally normal results (Tachikawa M et al. J Biol Chem, 2012 Mar;287:8398-406). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004702293 SCV005205202 uncertain significance not specified 2024-06-14 criteria provided, single submitter clinical testing Variant summary: FKTN c.557A>G (p.His186Arg) results in a non-conservative amino acid change located in the Ribitol-5-phosphate transferase FKTN, N-terminal domain (IPR045587) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251212 control chromosomes. c.557A>G has been reported in the literature in the homozygous state in an individual affected with classic Walker-Warburg Syndrome (Manzini_2008). These data indicate that the variant may be associated with disease. At least one functional study found that the variant protein was retained in the ER as opposed to localizing to the golgi, but that it also retained the activity responsible for -DG glycosylation similar to that of the WT protein (Tachikawa_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18752264, 22275357). ClinVar contains an entry for this variant (Variation ID: 554414). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005046885 SCV005679627 likely pathogenic 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 without intellectual disability), type B4 2024-06-24 criteria provided, single submitter clinical testing

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