Submissions for variant NM_014714.4(IFT140):c.386T>G (p.Leu129Trp)

gnomAD frequency: 0.00001  dbSNP: rs773768491

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421972	SCV000534454	uncertain significance	not provided	2016-12-20	criteria provided, single submitter	clinical testing	The L129W variant in the IFT140 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L129W variant was not observed in approximately 6,500 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 L129W 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 where amino acids with similar properties to Leucine 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. We interpret L129W as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861628	SCV002133910	likely pathogenic	Saldino-Mainzer syndrome	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 129 of the IFT140 protein (p.Leu129Trp). This variant is present in population databases (rs773768491, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 31047384, 31736247; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 391396). 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) has been performed at Invitae 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002506076	SCV002815687	uncertain significance	Saldino-Mainzer syndrome; Retinitis pigmentosa 80	2022-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155180	SCV003844929	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: IFT140 c.386T>G (p.Leu129Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251092 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in IFT140 causing Retinitis Pigmentosa (8e-05 vs 0.00063), allowing no conclusion about variant significance. c.386T>G has been reported in the literature in individuals affected with Retinitis Pigmentosa (example: Hariri_2018 and Zenteno_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003902618	SCV004723779	uncertain significance	IFT140-related disorder	2023-12-14	no assertion criteria provided	clinical testing	The IFT140 c.386T>G variant is predicted to result in the amino acid substitution p.Leu129Trp. This variant was reported in compound heterozygous state in two individuals with retinal dystrophy (Table 1, Hariri et al. 2018. PubMed ID: 31047384; Table 2, Zenteno et al. 2019. PubMed ID: 31736247). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-1642573-A-C), including one homozygote. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.