ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.1565G>A (p.Gly522Glu) (rs199826737)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Medical Genetics, INSERM RCV000626462 SCV000746989 pathogenic Saldino-Mainzer syndrome 2018-01-01 criteria provided, single submitter research
Broad Institute Rare Disease Group, Broad Institute 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
Invitae RCV000626462 SCV001373927 pathogenic Saldino-Mainzer syndrome 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 522 of the IFT140 protein (p.Gly522Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs199826737, ExAC 0.02%). This variant has been observed in individual(s) with Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, or retinitis pigmentosa (PMID: 23418020, 29688594, 26766544). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97054). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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
OMIM RCV000083298 SCV000115378 pathogenic Short-rib thoracic dysplasia without polydactyly 2013-05-01 no assertion criteria provided literature only
Institute of Human Genetics, Klinikum rechts der Isar RCV000626462 SCV001162812 pathogenic Saldino-Mainzer syndrome 2019-02-27 no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV001542691 SCV001760357 likely pathogenic Retinitis pigmentosa 80 no assertion criteria provided clinical testing

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