ClinVar Miner

Submissions for variant NM_001079802.2(FKTN):c.668C>T (p.Thr223Ile) (rs116105846)

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Total submissions: 7
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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 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000251420 SCV000319575 likely benign Cardiovascular phenotype 2019-02-20 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Inc RCV000710134 SCV000613319 likely benign not provided 2018-02-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000361387 SCV001442645 likely benign not specified 2020-10-19 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-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 in an individual affected with sick sinus syndrome (Celestino-Soper_2015). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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