ClinVar Miner

Submissions for variant NM_001291303.3(FAT4):c.4169T>C (p.Ile1390Thr)

gnomAD frequency: 0.00016  dbSNP: rs201934636
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001307225 SCV001496629 uncertain significance not provided 2022-08-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1390 of the FAT4 protein (p.Ile1390Thr). This variant is present in population databases (rs201934636, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1009702). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAT4 protein function. 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.
GeneDx RCV001307225 SCV001778191 uncertain significance not provided 2020-09-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001307225 SCV002525601 uncertain significance not provided 2020-05-26 criteria provided, single submitter clinical testing The p.Ile1390Thr (c.4169T>C, rs201934636) variant in exon 2 of FAT4 substitutes the isoleucine at position 1390 with threonine. This variant has not been reported as a pathogenic change in the medical literature or patient databases (Human Gene Mutation Database nor ClinGen). This variant is present in large population cohorts at a very low frequency (57 of 280,666 alleles; Genome Aggregation Database v2.1; GRCh37 chr4:126241735). This is a semi-conserved residue and some in silico tools predict this change is damaging (DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI and SIFT), while others predict this change is tolerated (DEOGEN2, MVP and REVEL).

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