Submissions for variant NM_014714.4(IFT140):c.1377G>A (p.Trp459Ter)

gnomAD frequency: 0.00006  dbSNP: rs140039128

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704469	SCV000833420	pathogenic	Saldino-Mainzer syndrome	2024-06-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp459*) in the IFT140 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant is present in population databases (rs140039128, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 26216056). ClinVar contains an entry for this variant (Variation ID: 580815). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001535954	SCV001752615	pathogenic	Saldino-Mainzer syndrome; Retinitis pigmentosa 80	2024-04-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001724143	SCV001950285	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Trp459Ter variant in IFT140 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788137	SCV005400151	pathogenic	Renal cyst	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 80 (MIM#617781), short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) and cystic kidney disease (MONDO:0002473), IFT140-related (PMID: 34890546). (I) 0108 - This gene is associated with both recessive and dominant disease. Retinitis pigmentosa 80 (MIM#617781) and short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) are inherited in an autosomal recessive manner, while cystic kidney disease (MONDO#0002473), IFT140-related is inherited in an autosomal dominant manner (OMIM, PMID: 34890546). (I) 0112 - The dominant condition associated with this gene may have incomplete penetrance. Parents of children with short-rib thoracic dysplasia 9 with or without polydactyly, who carry a single pathogenic variant that has also previously been associated with the dominant cystic kidney disease phenotype, have been reported as unaffected (PMID: 34890546). However these parents weren't specifically assessed for cystic kidney disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (22 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). These variants have been reported for both dominant and recessive disease (PMID: 34890546). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and has been observed as compound heterozygous in at least one individual with retinitis pigmentosa, and as a single heterozygous variant in several families with autosomal dominant cystic kidney disease (PMIDs: 26216056, 31736247, 34890546). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed in two affected individuals from one family with autosomal dominant cystic kidney disease (PMID: 34890546). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003411642	SCV004114463	pathogenic	IFT140-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The IFT140 c.1377G>A variant is predicted to result in premature protein termination (p.Trp459*). This variant has been reported to be pathogenic for autosomal recessive retinitis pigmentosa and the autosomal dominant polycystic kidney-spectrum phenotype (Xu et al. 2015. PubMed ID: 26216056; Senum et al. 2022. PubMed ID: 34890546). This variant is reported in 0.22% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in IFT140 are expected to be pathogenic. This variant is interpreted as pathogenic for both autosomal dominant and autosomal recessive IFT140-related disorders.