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

gnomAD frequency: 0.00009  dbSNP: rs201893408

Total submissions: 18

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 Laboratory Services, Illumina	RCV000283682	SCV000475346	pathogenic	TMEM67-related disorder	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	Familial aplasia of the vermis; Oligohydramnios; Renal cyst	2014-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000479077	SCV000567559	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate C615R results in improper localization of the TMEM67 protein within cells (Gunay-Aygun et al., 2009; Abdelhamed et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19778711, 19508969, 19540516, 26035863, 21866095, 19466712, 21068128, 23559409, 26673778, 28125082, 10508989, 25729630, 29956005, 29146704, 29974258, 32574212, 27491411, 26092869, 20607301, 28497568, 19574260, 20232449, 25920555, 32939031, 34356094, 34958143, 35627109, 36090483)
Invitae	RCV000534533	SCV000634630	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 615 of the TMEM67 protein (p.Cys615Arg). This variant is present in population databases (rs201893408, gnomAD 0.03%). This missense change has been observed in individual(s) with TMEM67-related ciliopathies (PMID: 19508969, 19540516, 19574260, 20607301, 21068128, 23559409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TMEM67 function (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; Kidney damage; 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	COACH syndrome 1; 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
Revvity Omics, Revvity	RCV000479077	SCV002022349	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000283682	SCV004046149	pathogenic	TMEM67-related disorder		criteria provided, single submitter	clinical testing	This variant results in a c.1600T>C (p.Cys534Arg) change in an alternate TMEM67 transcript NM_001142301. This variant has been previously reported as a compound heterozygous and homozygous change in patients with nephronophthisis, Joubert syndrome, and Meckel syndrome (PMID: 19574260, 19508969, 21068128, 23559409, 19540516, 20607301, 19466712, 17397051, 21866095). Functional studies demonstrated that the p.Cys615Arg variant prevents localization and disrupts the ability of TMEM67 to regulate Wnt signaling (PMID: 19540516, 26035863). The c.1843T>C (p.Cys615Arg) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The c.1843T>C (p.Cys615Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01% (40/282,762). Based on the available evidence, the c.1843T>C (p.Cys615Arg) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000283682	SCV004114975	pathogenic	TMEM67-related disorder	2022-10-14	criteria provided, single submitter	clinical testing	The TMEM67 c.1843T>C variant is predicted to result in the amino acid substitution p.Cys615Arg. This variant has previously been identified in the compound heterozygous or homozygous state in multiple individuals with TMEM67-related disorders, including Meckel syndrome, Joubert syndrome, and nephronophthisis (Tallila et al. 2009. PubMed ID: 19466712; Otto et al. 2009. PubMed ID: 19508969; Chaki et al. 2011. PubMed ID: 21866095; Halbritter et al. 2013. PubMed ID: 23559409; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-94808198-T-C). Taken together, we interpret this variant as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000479077	SCV005198802	pathogenic	not provided	2022-07-13	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	not provided	Nephronophthisis		no assertion provided	literature only