Submissions for variant NM_001079802.2(FKTN):c.482A>G (p.His161Arg)

dbSNP: rs727502848

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000149978	SCV000196834	uncertain significance	not provided	2014-09-02	criteria provided, single submitter	clinical testing	p.His161Arg (CAC>CGC): c.482 A>G in exon 6 of the FKTN gene (NM_001079802.1) Although rare, mutations in the FKTN gene have been reported in association with isolated DCM (Murakami T et al., 2006). To date, all individuals reported with apparently isolated DCM caused by mutations in the FKTN gene have been compound heterozygous for a missense mutation and a 3kb retrotransposal insertion in the 3'UTR. The 3kb retrotransposal insertion is common to individuals of Japanese ancestry (Arimura T et al., 2009; Murakami T et al., 2006). The H161R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H161R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H161R substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, only one missense mutation in a nearby residue (A170E) has been reported in association with muscular dystrophy. Additionally, H161R is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821201	SCV000961950	uncertain significance	Walker-Warburg congenital muscular dystrophy	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 161 of the FKTN protein (p.His161Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC 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: 162570). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.