Submissions for variant NM_001079802.2(FKTN):c.397A>G (p.Met133Val) (rs569778463)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000357115	SCV000476421	uncertain significance	Dilated Cardiomyopathy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000264741	SCV000476422	uncertain significance	Fukuyama congenital muscular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000634069	SCV000755347	uncertain significance	Walker-Warburg congenital muscular dystrophy	2019-05-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 133 of the FKTN protein (p.Met133Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs569778463, ExAC 0.2%). This variant has not been reported in the literature in individuals with FKTN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Met133Thr) has been reported in an individual affected with Fukuyama-type congenital muscular dystrophy (PMID: 17597323). 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.