ClinVar Miner

Submissions for variant NM_024582.4(FAT4):c.5401C>T (p.Arg1801Trp) (rs201887525)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497799 SCV000590090 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FAT4 gene. The R1801W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1801W variant is observed in 22/66,720 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1801W 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000497799 SCV001247398 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Invitae RCV000497799 SCV001561275 uncertain significance not provided 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1801 of the FAT4 protein (p.Arg1801Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs201887525, ExAC 0.05%). This variant has not been reported in the literature in individuals with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 432372). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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