Submissions for variant NM_153704.6(TMEM67):c.1843T>C (p.Cys615Arg) (rs201893408)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program,University of Washington	RCV000001452	SCV000256497	pathogenic	Joubert syndrome 6	2015-02-23	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000283682	SCV000475346	pathogenic	TMEM67-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of available literature, the TMEM67 c.1843T>C (p.Cys615Arg) missense variant has been identified in a homozygous state in seven patients and in a compound heterozygous state in at least 11 patients with TMEM67-related disorders, which include the phenotypically overlapping disorders nephronophthisis, Joubert syndrome, and Meckel syndrome (Otto et al. 2009; Tallili et al. 2009; Gunay-Aygun et al. 2009; Seeman et al. 2010; Halbritter et al. 2013). The p.Cys615Arg variant was absent from 484 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cell lines demonstrated that the p.Cys615Arg variant prevents the localization of the protein to cilia and disrupts the ability of TMEM67 to regulate Wnt signaling (Gunay-Aygun et al. 2009; Abdelhamed et al. 2015). Based on the collective evidence, the p.Cys615Arg variant is classified as pathogenic for TMEM67-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415055	SCV000493011	likely pathogenic	Joubert syndrome; Oligohydramnios; Renal cyst	2014-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000479077	SCV000567559	pathogenic	not provided	2018-10-09	criteria provided, single submitter	clinical testing	The C615R pathogenic variant in the TMEM67 gene has been reported previously in association with a variety of TMEM67-related disorders including nephronophthisis, Meckel syndrome, and Joubert syndrome (Otto et al., 2009; Tallila et al., 2009; Chaki et al., 2011; Halbritter et al., 2013). Functional studies suggest that C615R results in improper localization of the TMEM67 protein within cells (Gunay-Aygun et al., 2009). The C615R variant is observed in 29/66,714 (0.04%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C615R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, C615R is considered to be a pathogenic variant.
Invitae	RCV000534533	SCV000634630	pathogenic	Joubert syndrome; Meckel-Gruber syndrome	2020-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 615 of the TMEM67 protein (p.Cys615Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs201893408, ExAC 0.04%). This variant has been reported to segregate with TMEM67-related ciliopathies in several families (PMID: 20607301, 19540516, 19508969). It has also been reported in many affected individuals, some of whom were homozygous for this variant (PMID: 19574260, 19508969, 21068128, 23559409, 19540516). ClinVar contains an entry for this variant (Variation ID: 1383). Experimental studies have shown that the TMEM67 protein with this missense change is mislocalized in cells, and cannot restore normal Wnt signaling in cells lacking endogenous TMEM67 (PMID: 19540516, 26035863). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000623857	SCV000742786	pathogenic	Inborn genetic diseases	2017-08-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000627004	SCV000747707	likely pathogenic	Congenital ocular coloboma; Global developmental delay; Visual impairment; Nystagmus; Absent speech; Barrel-shaped chest; Nephropathy; Cerebellar vermis hypoplasia; Tremor; Pancreatitis; Cerebellar malformation; Peritonitis; Infantile muscular hypotonia; Intellectual disability, severe	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763610	SCV000894456	pathogenic	Joubert syndrome with hepatic defect; Joubert syndrome 6; Meckel syndrome, type 3; Bardet-Biedl syndrome 14; Nephronophthisis 11	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001197497	SCV001368263	likely pathogenic	RHYNS syndrome	2019-10-03	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute	RCV000001452	SCV001427181	pathogenic	Joubert syndrome 6	2019-02-10	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_153704.5(TMEM67):c.1843T>C, has been identified in exon 18 of 28 of the TMEM67 gene. The variant is predicted to result in a major amino acid change from cysteine to arginine at position 615 of the protein (NP_714915.3(TMEM67):p.(Cys615Arg)). The cysteine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the meckelin transmembrane functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0142% (40 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in several families with TMEM67-related ciliopathies (ClinVar). Transfected IMCD3 cells displayed impaired protein localization within the mid-cell region, and did not localize to the apical cell surface (Gunay-Aygun, M., et al. (2009)). Subsequent analysis of parental samples indicated this variant was maternally inherited. Based on current information, this variant has been classified as PATHOGENIC.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000479077	SCV001446478	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000001451	SCV000021601	pathogenic	Nephronophthisis 11	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000001452	SCV000021602	pathogenic	Joubert syndrome 6	2009-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000234823	SCV000292015	pathogenic	Nephronophthisis	2016-02-10	no assertion criteria provided	literature only