Submissions for variant NM_014714.4(IFT140):c.2500C>T (p.Arg834Ter)

dbSNP: rs777399400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381246	SCV001579565	pathogenic	Saldino-Mainzer syndrome	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg834*) 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 (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with IFT140-related conditions. ClinVar contains an entry for this variant (Variation ID: 1069388). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789564	SCV005400154	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 and v3) <0.01 (4 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 in families with later onset autosomal dominant polycystic kidney disease (PMID: 34890546) and autosomal recessive IFT140-related conditions (PMIDs: 22503633, 26968735). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified as pathogenic by a clinical laboratory in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005005913	SCV005642789	likely pathogenic	Saldino-Mainzer syndrome; Retinitis pigmentosa 80	2024-06-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416302	SCV004107108	pathogenic	IFT140-related disorder	2024-06-22	no assertion criteria provided	clinical testing	The IFT140 c.2500C>T variant is predicted to result in premature protein termination (p.Arg834*). This variant was reported in an individual with autosomal dominant polycystic kidney disease (Patient UK8 in Senum et al. 2022. PubMed ID: 34890546). This variant is reported in 0.0017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Heterozygous loss-of-function variants in IFT140 have recently been associated with autosomal dominant polycystic kidney disease and segregation analysis in many unrelated families supports this mode of inheritance (Senum et al 2022. PubMed ID: 34890546). This variant is interpreted as pathogenic.