Submissions for variant NM_001079802.2(FKTN):c.920G>A (p.Arg307Gln)

gnomAD frequency: 0.00001  dbSNP: rs119463992

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724028	SCV000700705	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036532	SCV001199900	pathogenic	Walker-Warburg congenital muscular dystrophy	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 307 of the FKTN protein (p.Arg307Gln). This variant is present in population databases (rs119463992, gnomAD 0.01%). This missense change has been observed in individual(s) with FKTN-related conditions (PMID: 17044012, 19179078, 19396839, 25821721, 30060766). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKTN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FKTN function (PMID: 26923585). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192872	SCV001361296	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	2019-05-02	criteria provided, single submitter	clinical testing	Variant summary: FKTN c.920G>A (p.Arg307Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249118 control chromosomes (gnomAD). c.920G>A has been reported in the literature in multiple affected individuals (Ceyhan-Birsoy_2015, Godfrey_2007, Johnson_2018, Yis_2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003466793	SCV004199742	pathogenic	Dilated cardiomyopathy 1X	2023-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000724028	SCV005078149	likely pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Has been reported in individuals with a dystroglycinopathy phenotype (Godfrey et al., 2006; Godfrey, et al., 2007; Vuillaumier-Barrot et al., 2009; Johnson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies in CHO cells showed that this variant does not affect FKTN expression or localization (Godfrey et al., 2006); This variant is associated with the following publications: (PMID: 31589614, 17044012, 25821721, 32528171, 20961758, 19299310, 24144914, 19833706, 26923585, 19266496, 19396839, 32906206, 30060766, 17878207, 19179078, 30564623)
OMIM	RCV000003362	SCV000023520	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2M	2009-05-26	no assertion criteria provided	literature only
OMIM	RCV001254647	SCV001430679	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4	2009-05-26	no assertion criteria provided	literature only