ClinVar Miner

Submissions for variant NM_024582.4(FAT4):c.8072C>T (p.Ser2691Leu) (rs148918820)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766651 SCV000581920 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FAT4 gene. The S2691L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S2691L variant is observed in 21/66,620 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S2691L 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 analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000493812 SCV000594748 uncertain significance not specified 2016-12-09 criteria provided, single submitter clinical testing
Invitae RCV000766651 SCV001566704 uncertain significance not provided 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2691 of the FAT4 protein (p.Ser2691Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs148918820, ExAC 0.03%). This variant has not been reported in the literature in individuals with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 429367). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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