ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.472C>T (p.Arg158Trp)

gnomAD frequency: 0.00001  dbSNP: rs755315693
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000487511 SCV000575025 likely pathogenic not provided 2017-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001584198 SCV001821384 uncertain significance not specified 2021-08-24 criteria provided, single submitter clinical testing Variant summary: IFT140 c.472C>T (p.Arg158Trp) results in a non-conservative amino acid change located in the WD40/YVTN repeat-like containing superfamily domain (IPR015943) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251318 control chromosomes. c.472C>T has been reported in the literature as a compound heterozygous genotype, in at-least three individuals from comprehensively genotyped cohorts (i.e., WES/comprehensive panel based targeted NGS analysis) affected with Retinal dystrophies and/or inherited retinal disease (IRD) (example, Weisschuh_2016 and Weisschuh_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic presumably utilizing at-least one citation included in the context of this evaluation (Weisschuh_2016). Based on the evidence outlined above, until additional clinically diagnosed patients supported by conclusive functional evidence is identified, the variant was classified as VUS-possibly pathogenic.
Invitae RCV001856885 SCV002205883 uncertain significance Saldino-Mainzer syndrome 2022-08-22 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 425084). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26766544, 32531858). This variant is present in population databases (rs755315693, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 158 of the IFT140 protein (p.Arg158Trp).

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