ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.1727G>A (p.Arg576Gln)

gnomAD frequency: 0.00003  dbSNP: rs373111085
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174924 SCV000226326 uncertain significance not provided 2015-02-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001234939 SCV001407600 pathogenic Saldino-Mainzer syndrome 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 576 of the IFT140 protein (p.Arg576Gln). This variant is present in population databases (rs373111085, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of IFT140-related conditions (PMID: 22503633; internal data). ClinVar contains an entry for this variant (Variation ID: 194537). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IFT140 protein function. This variant disrupts the p.Arg576 amino acid residue in IFT140. Other variant(s) that disrupt this residue have been observed in individuals with IFT140-related conditions (PMID: 28512305; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002478565 SCV002775185 uncertain significance Saldino-Mainzer syndrome; Retinitis pigmentosa 80 2024-01-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004752773 SCV005354215 uncertain significance IFT140-related disorder 2024-09-26 no assertion criteria provided clinical testing The IFT140 c.1727G>A variant is predicted to result in the amino acid substitution p.Arg576Gln. This variant in the heterozygous condition has been reported in an individual with Mainzer-Saldino syndrome (Perrault et al 2012. PubMed ID: 22503633). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. A different variant affecting the same amino acid (p.Arg576Leu) has been reported as uncertain in individual with congenital heart disease, who also carried a second variant in this gene (Table S10, Alankarage et al. 2019. PubMed ID: 30293987) and found in the compound heterozygous condition along with a second variant in this gene in another individual with retinitis pigmentosa (Huang et al. 2017. PubMed ID: 28512305). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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