Submissions for variant NM_014714.4(IFT140):c.1565G>A (p.Gly522Glu)

gnomAD frequency: 0.00009  dbSNP: rs199826737

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000626462	SCV000746989	pathogenic	Saldino-Mainzer syndrome	2018-01-01	criteria provided, single submitter	research
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000626462	SCV001162812	pathogenic	Saldino-Mainzer syndrome	2019-02-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000626462	SCV001164385	uncertain significance	Saldino-Mainzer syndrome	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Gly522Glu variant in IFT140 was identified by our study in one individual in the compound heterozygous state, with another VUS, with Short-Rib Thoracic Dysplasia with or without Polydactyly. This variant has been seen in 0.02684% (34/126700) of European (non-Finnish) chromosomes and 0.01970% (2/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199826737). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has been reported in the compound heterozygous state in four individuals (including two Serbians) with IFT140-associated diseases (PMID: 29688594). The presence of this variant in combination with reported pathogenic and likely pathogenic variants and in an individual with Short-Rib Thoracic Dysplasia with or without Polydactyly increases the likelihood that the p.Gly522Glu variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3 (Richards 2015).
Blueprint Genetics	RCV001075445	SCV001241068	pathogenic	Retinal dystrophy	2018-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000626462	SCV001373927	pathogenic	Saldino-Mainzer syndrome	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 522 of the IFT140 protein (p.Gly522Glu). This variant is present in population databases (rs199826737, gnomAD 0.03%). This missense change has been observed in individual(s) with Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, or retinitis pigmentosa (PMID: 23418020, 26766544, 29688594). 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: 97054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IFT140 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268554	SCV001447554	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001268554	SCV002011678	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001268554	SCV002526374	likely pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 34758253, 22503633, 26216056, 26766544, 32007091, 31397098, 28741273, 31964843, 34890546, 29688594, Leonhard2023[FunctionalStudy], 23418020, 37734845, 37628605)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509205	SCV002819819	likely pathogenic	Retinitis pigmentosa	2022-12-25	criteria provided, single submitter	clinical testing	Variant summary: IFT140 c.1565G>A (p.Gly522Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251382 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IFT140 causing Retinitis Pigmentosa (0.00013 vs 0.00063), allowing no conclusion about variant significance. c.1565G>A has been reported in the literature as a biallelic compound heterozygous genotype in multiple comprehensively genotyped individuals affected with features of IFT140-related disorders such as Jeune asphyxiating thoracic dystrophy (JATD), inherited retinal disease (IRD) and Mainzer-Saldino syndrome (MSS) (example, Perrault_2012, Schmidts_2013, Weisschuh_2020, Geoffroy_2018, Senum_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=6; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001542691	SCV004045966	likely pathogenic	Retinitis pigmentosa 80	2023-01-05	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000626462	SCV005400152	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 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) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (39 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous in several individuals with syndromic skeletal dysplasia and renal abnormalities (PMIDs: 32007091, 34596737, 23418020). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000083298	SCV000115378	pathogenic	Short-rib thoracic dysplasia without polydactyly	2013-05-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542691	SCV001760357	likely pathogenic	Retinitis pigmentosa 80		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398688	SCV004104051	likely pathogenic	IFT140-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The IFT140 c.1565G>A variant is predicted to result in the amino acid substitution p.Gly522Glu. This variant was reported in the compound heterozygous state along with a second potentially causative variant in two unrelated individuals with Jeune asphyxiating thoracic dystrophy (Schmidts et al. 2013. PubMed ID: 23418020) and in two unrelated individuals with cranioectodermal dysplasia (Walczak-Sztulpa et al. 2020. PubMed ID: 32007091). This variant was also reported in one patient with Mainzer-Saldino syndrome, although a second causative variant was not identified (Perrault et al. 2012. PubMed ID: 22503633). In addition, this variant was also reported in an individual with the autosomal dominant polycystic kidney-spectrum phenotype (Senum et al. 2021. PubMed ID: 34890546). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Of note, loss-of-function has been known to be the disease-causing mechanism for both autosomal recessive and dominant IFT140-related disorders (https://search.clinicalgenome.org/kb/genes/HGNC:29077; Senum et al. 2022. PubMed ID: 34890546). Therefore, this variant is interpreted as likely pathogenic for both autosomal recessive and dominant IFT140-related disorders.