ClinVar Miner

Submissions for variant NM_006731.2(FKTN):c.1159G>A (p.Gly387Arg) (rs148975262)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723916 SCV000202714 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing
Invitae RCV000227560 SCV000285814 uncertain significance Walker-Warburg congenital muscular dystrophy 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 387 of the FKTN protein (p.Gly387Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs148975262, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a FKTN-related disease. ClinVar contains an entry for this variant (Variation ID: 167070). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000339058 SCV000476429 uncertain significance Dilated Cardiomyopathy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000406528 SCV000476430 uncertain significance Fukuyama congenital muscular dystrophy 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000723916 SCV000566772 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The G387R variant in the FKTN gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed, in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiac genetic testing at GeneDx. The G387R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Furthermore, the G387R variant is observed in 102/126214 (0.08%) alleles from individuals of non-Finnish European ancestry, and 120/276108 total alleles in large population cohorts (Lek et al., 2016). We interpret G387R as a variant of uncertain significance.
Ambry Genetics RCV000620716 SCV000735845 uncertain significance Cardiovascular phenotype 2018-08-09 criteria provided, single submitter clinical testing Insufficient evidence
Athena Diagnostics Inc RCV000723916 SCV001143894 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing

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