ClinVar Miner

Submissions for variant NM_014714.4(IFT140):c.634G>A (p.Gly212Arg)

gnomAD frequency: 0.00008  dbSNP: rs201188361
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255441 SCV000322476 pathogenic not provided 2022-04-01 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Perrault et al., 2012; Helm et al., 2017); Variant impacting the last nucleotide of an exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 30924848, 29068549, 30773290, 28724397, 29688594, 28559085, 32371413, 28288023, 22503633, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp RCV000024363 SCV000640305 pathogenic Saldino-Mainzer syndrome 2023-08-27 criteria provided, single submitter clinical testing This variant is present in population databases (rs201188361, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects IFT140 function (PMID: 22503633, 28724397). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 31683). This missense change has been observed in individual(s) with Mainzer-Saldino syndrome, Jeune synrome, or Senior-Loken syndrome (PMID: 22503633, 28559085, 28724397). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the IFT140 protein (p.Gly212Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University RCV000024363 SCV000746987 pathogenic Saldino-Mainzer syndrome 2018-01-01 criteria provided, single submitter research
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University RCV000626465 SCV000746992 pathogenic Retinal ciliopathy due to mutation in the retinitis pigmentosa-1 gene 2018-01-01 criteria provided, single submitter research
Illumina Laboratory Services, Illumina RCV000024363 SCV000915705 likely pathogenic Saldino-Mainzer syndrome 2019-01-10 criteria provided, single submitter clinical testing The IFT140 c.634G>A (p.Gly212Arg) variant has been reported in two studies and was found in four probands, including one sibling-pair, one in a homozygous state and three in a compound heterozygous state (Perrault et al. 2012; Helm et al. 2017). One of these probands, who carried the splice-site mutation on the other allele, was clinically diagnosed with Jeune syndrome. Jeune syndrome has overlapping symptoms with Mainzer-Saldino syndrome with the additional phenotype of asphyxiating thoracic dystrophy. The p.Gly212Arg variant is reported at a frequency of 0.000095 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies of the p.Gly212Arg variant in retinal pigment epithelial cells showed changes to the cellular localization of the variant protein (Perrault et al. 2012). In vitro analysis in lymphocyte cells found that the p.Gly212Arg variant affected splicing of exon 6 (Helm et al. 2017). Based on the evidence, the p.Gly212Arg variant is classified as likely pathogenic for Mainzer-Saldino syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital RCV001249674 SCV001423625 pathogenic Saldino-Mainzer syndrome; Retinitis pigmentosa 80 2018-01-31 criteria provided, single submitter clinical testing [ACMG/AMP: PVS1, PS3, PM2, PM3, PP3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Fulgent Genetics, Fulgent Genetics RCV001249674 SCV002809847 pathogenic Saldino-Mainzer syndrome; Retinitis pigmentosa 80 2022-04-14 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255441 SCV003818299 pathogenic not provided 2022-07-15 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000255441 SCV004133725 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing IFT140: PM3:Very Strong, PM2, PP3
OMIM RCV000024363 SCV000045656 pathogenic Saldino-Mainzer syndrome 2012-05-04 no assertion criteria provided literature only
Dan Cohn Lab, University Of California Los Angeles RCV000515934 SCV000612040 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328311 SCV001449335 pathogenic Nephronophthisis 2018-10-25 no assertion criteria provided clinical testing This patient is heterozygous for a c.634G>A (p.Gly212Arg) in the IFT140 gene. This variant has been previously reported in conjunction with a second pathogenic IFT140 mutation in patients with Mainzer-Saldino syndrome (MSS) and Jeune syndrome .Functional studies have shown that this variant affects IFT140 cell localization and therefore this variant is considered to be pathogenic (Perrault et al. 2012, Am. J. Hum.Genet 90, 864-870).
University of Washington Center for Mendelian Genomics, University of Washington RCV000515934 SCV001479393 likely pathogenic Jeune thoracic dystrophy no assertion criteria provided research
Yale Center for Mendelian Genomics, Yale University RCV000024363 SCV002106584 pathogenic Saldino-Mainzer syndrome 2019-02-14 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004752723 SCV005363836 pathogenic IFT140-related disorder 2024-09-06 no assertion criteria provided clinical testing The IFT140 c.634G>A variant is predicted to result in the amino acid substitution p.Gly212Arg. This variant has been reported in multiple individuals with IFT140-related ciliopathy (for examples, see Perrault et al. 2012. PubMed ID: 22503633; Bayat. 2017. PubMed ID: 28288023). With a second pathogenic variant on the opposite chromosome (in trans), the variant was documented to be causative for Mainzer-Saldino Syndrome and Jeune Syndrome in an adult patient and a child patient, respectively (Perrault et al. 2012. PubMed: 22503633). It has also been found in the compound heterozygous state in an individual with cleft palate (Wilson et al. 2023. PubMed ID: 37010288). This variant has been shown to disrupt splicing in an in vivo model, leading to loss of function (Helm et al. 2017. PubMed ID: 28724397). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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