Submissions for variant NM_014714.4(IFT140):c.2577+25G>A

dbSNP: rs1423102192

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000626460	SCV000746986	pathogenic	Saldino-Mainzer syndrome	2018-01-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779029	SCV002015023	likely pathogenic	Retinitis pigmentosa	2021-10-22	criteria provided, single submitter	clinical testing	Variant summary: IFT140 c.2577+25G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a 5' donor site. Three predict the variant strengthens a cryptic 5' donor site. One predict the variant creates a 5' donor site. Patient RNA analysis confirmed that a novel donor splice site within the intron 20 resulted in the incorporation of 21 additional base pairs (r.2577_2578insGTGAGGGGCGCCCGCCATGGG) that are predicted to add seven new amino acids to the protein sequence (p.Leu859_Glu860insValArgGlyAlaArgHisGly; Geoffroy_2018). The variant was absent in 125168 control chromosomes. c.2577+25G>A has been reported in the literature in two siblings affected with retinitis pigmentosa, short stature, brachydactyly, moderate renal failure and overweight (Geoffroy_2018). In this same study, functional analysis on the patients cells further revealed a reduced level of ciliated cells and mislocalization of the IFT140 mutant away from the cilia base. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000626460	SCV005400148	likely pathogenic	Saldino-Mainzer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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) (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) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies have shown that this variant creates a novel donor splice site in intron 20 which leads to the incorporation of 21 additional base pairs. This is predicted to result in the in frame incorporation of seven amino acids to the protein sequence (PMID: 29688594). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0705 - No comparable splice or in frame insertion variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar, and has been observed as compound heterozygous with an exon 27-30 duplication in two siblings with a Bardet-Biedl like phenotype (PMID: 29688594). (SP) 1010 - Functional evidence for this variant is inconclusive. Immunofluorescence studies in patient cells have shown that this variant leads to a significant decrease in cilium formation and the mislocalisation of IFT140 protein (PMID: 29688594). However, as the patients were compound heterozygous for this and another IFT140 variant the contribution of this variant alone cannot be determined from this study. (SP) 1201 - Heterozygous variant detected in trans with a pathogenic heterozygous variant (NM_014714.3(IFT140):c.1565G>A; p.(Gly522Glu)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign