ClinVar Miner

Submissions for variant NM_024582.4(FAT4):c.9596A>G (p.Tyr3199Cys) (rs115895451)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413428 SCV000491927 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing The Y3199C variant in the FAT4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed with significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y3199C 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. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available evidence, we interpret Y3199C as a variant of uncertain significance.
Invitae RCV001317235 SCV001507889 uncertain significance not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 3199 of the FAT4 protein (p.Tyr3199Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs115895451, ExAC 0.1%). This variant has not been reported in the literature in individuals with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 373340). 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.

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