Submissions for variant NM_001079802.2(FKTN):c.668C>T (p.Thr223Ile)

gnomAD frequency: 0.00224  dbSNP: rs116105846

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000361387	SCV000196831	benign	not specified	2016-07-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001083098	SCV000285820	benign	Walker-Warburg congenital muscular dystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251420	SCV000319575	likely benign	Cardiovascular phenotype	2019-02-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000361387	SCV000337567	benign	not specified	2015-11-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000361387	SCV000594788	likely benign	not specified	2016-05-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000361387	SCV000613319	likely benign	not specified	2020-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000361387	SCV001442645	benign	not specified	2021-11-15	criteria provided, single submitter	clinical testing	Variant summary: FKTN c.668C>T (p.Thr223Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251290 control chromosomes, predominantly at a frequency of 0.0086 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKTN causing Dilated Cardiomyopathy phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.668C>T has been reported in the literature as a VUS in an individual affected with sick sinus syndrome (example, Celestino-Soper_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MYBPC3 c.3330+5G>C), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004532671	SCV004726211	likely benign	FKTN-related disorder	2019-06-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).