ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.1010-1G>A

gnomAD frequency: 0.00006  dbSNP: rs770185023
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000326779 SCV000330838 pathogenic not provided 2022-03-30 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 34890546, 29068549)
Invitae RCV001055096 SCV001219466 pathogenic Saldino-Mainzer syndrome 2023-12-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the IFT140 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant is present in population databases (rs770185023, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). 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: 280884). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376438 SCV001573577 pathogenic Retinitis pigmentosa 80 2021-04-08 criteria provided, single submitter research The IFT140 c.1010-1G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002503978 SCV002814146 pathogenic Saldino-Mainzer syndrome; Retinitis pigmentosa 80 2022-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155145 SCV003844928 likely pathogenic Retinitis pigmentosa 2023-02-17 criteria provided, single submitter clinical testing Variant summary: IFT140 c.1010-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 247956 control chromosomes (gnomAD). c.1010-1G>A has been reported in the literature in individuals affected with asphyxiating thoracic dystrophy and craniosynostosis (examples: Zhang_2018 and Hyder_2021). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles RCV000516131 SCV000612039 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000516131 SCV001479392 likely pathogenic Jeune thoracic dystrophy no assertion criteria provided research

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