ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) (rs1057518064)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413732 SCV000491441 likely pathogenic not provided 2016-02-27 criteria provided, single submitter clinical testing The P726A variant in the IFT140 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P726A variant was not observed in approximately 6500 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 P726A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P726A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV001042480 SCV001206162 uncertain significance Saldino-Mainzer syndrome 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 726 of the IFT140 protein (p.Pro726Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IFT140-related conditions. ClinVar contains an entry for this variant (Variation ID: 372905). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328310 SCV001449334 uncertain significance Nephronophthisis 2018-10-25 no assertion criteria provided clinical testing This patient is also heterozygous for a variant of unknown clinical significance (VOUS), c.2176C>G (p.Pro726Ala) in the IFT140 gene. To our knowledge, this variant has not been previously reported in the literature. p.Pro726 is a highly conserved amino acid (up to 13 species). In silico analysis (Alamut Visual v2.4) using PolyPhen2, SIFT and MutationTaster all predict this variant to be pathogenic.

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