Submissions for variant NM_014714.4(IFT140):c.2399+1G>T

gnomAD frequency: 0.00006  dbSNP: rs376586707

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000024360	SCV001200458	pathogenic	Saldino-Mainzer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 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 (rs376586707, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with IFT140-related conditions (PMID: 22503633, 23418020, 26968735). ClinVar contains an entry for this variant (Variation ID: 31680). 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.
Blueprint Genetics	RCV001075306	SCV001240924	pathogenic	Retinal dystrophy	2017-12-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001536095	SCV001752805	pathogenic	Saldino-Mainzer syndrome; Retinitis pigmentosa 80	2022-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818178	SCV002064445	pathogenic	not provided	2021-06-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the IFT140 gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2399+1G>T. This sequence change is predicted to affect mRNA splicing and is likely to result in an absent or truncated protein. It has been described in the gnomAD database in the non-Finnish European subpopulation with a low frequency of 0.012% only (dbSNP rs376586707). This sequence change has been previously described in the compound heterozygous state in family and individuals with IFT140-related disorders (PMIDs: 22503633, 26968735, 23418020). Collectively, this evidence indicates that the c.2399+1G>T change is pathogenic.
GeneDx	RCV001818178	SCV002504221	pathogenic	not provided	2021-10-29	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed with a second variant on the opposite allele (in trans) in patients with Mainzer-Saldino syndrome or isolated retinal dystrophy in the published literature (Schmidts et al., 2013; Hull et al., 2016); This variant is associated with the following publications: (PMID: 31397098, 26968735, 28724397, 22503633, 29688594, 31980526, 31589614, 32037395, 23418020)
MGZ Medical Genetics Center	RCV000515584	SCV002581771	pathogenic	Retinitis pigmentosa 80	2021-11-11	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993751	SCV004812569	pathogenic	Autosomal dominant polycystic kidney disease	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in IFT140 occurs within the canonical splice donor site of intron 19. It is predicted to cause native donor site loss and cryptic donor creation leading to a one bp deletion resulting in a frameshift (exon 19/31) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 22282595, 34890546). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.04% (463/1,179,776 alleles) in the European (non-Finnish) population. This variant has been reported as a common cause of IFT140-related polycystic kidney disease (PKD) with a distinctive monoallelic phenotype of mild PKD with large cysts, limited kidney insufficiency, and few liver cysts (PMID: 34890546). The variant has been reported to segregate with PKD in multiple families (PMID: 34890546). This variant has been detected as compound heterozygous with a second pathogenic variant in at least two individuals with a ciliopathy phenotype (PMID: 22503633). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760343	SCV005368461	pathogenic	Polycystic kidney disease	2023-02-28	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD
OMIM	RCV000024360	SCV000045653	pathogenic	Saldino-Mainzer syndrome	2013-05-01	no assertion criteria provided	literature only
OMIM	RCV000515584	SCV000611640	pathogenic	Retinitis pigmentosa 80	2013-05-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003924859	SCV004738355	pathogenic	IFT140-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The IFT140 c.2399+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant along with another IFT140 variant has been reported to be causative for Mainzer-Saldino syndrome and Jeune syndrome (Perrault et al. 2012. PubMed ID: 22503633; Schmidts et al. 2013. PubMed ID: 23418020). It has also been reported along with a missense IFT140 variant in two siblings with retinal dystrophy (Hull et al. 2016. PubMed ID: 26968735). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt consensus splice donor sites in IFT140 are expected to be pathogenic. Of note, monoallelic IFT140 loss-of-function pathogenic variants have been reported to cause the autosomal dominant polycystic kidney-spectrum phenotype and this splicing variant is among the pathogenic changes found in this study (Senum et al. 2022. PubMed ID: 34890546). This variant is interpreted as pathogenic for both autosomal recessive and autosomal dominant IFT140-related disorders.