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

gnomAD frequency: 0.00008  dbSNP: rs201188361

Total submissions: 14

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)
Invitae	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