ClinVar Miner

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

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Total submissions: 11
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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 Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
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
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

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