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

gnomAD frequency: 0.00006  dbSNP: rs770185023

Total submissions: 7

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)
Labcorp Genetics (formerly Invitae), Labcorp	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