Submissions for variant NM_153704.6(TMEM67):c.622A>T (p.Arg208Ter)

gnomAD frequency: 0.00026  dbSNP: rs137853108

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000001443	SCV000249165	pathogenic	Joubert syndrome 6	2014-10-16	criteria provided, single submitter	clinical testing
UW Hindbrain Malformation Research Program, University of Washington	RCV000001443	SCV000256498	pathogenic	Joubert syndrome 6	2015-02-23	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000494327	SCV000331571	pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000334857	SCV000475327	pathogenic	TMEM67-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The TMEM67 c.622A>T (p.Arg208Ter) variant is a stop-gained variant and is predicted result in premature termination of the TMEM67 protein. Across a selection of available literature, the p.Arg208Ter variant has been identified in 12 patients with a phenotype of nephronophthisis, Joubert syndrome, or Meckel syndrome, including in a compound heterozygous state in nine patients and in a heterozygous state in three affected patients in whom a second variant was not identified, and in a heterozygous state in seven unaffected family members (Consugar et al. 2007; Khaddour et al. 2007; Otto et al. 2009; Halbritter et al. 2013). The p.Arg208Ter variant was absent from 388 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Arg208Ter 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.
Invitae	RCV000468558	SCV000552811	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg208*) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs137853108, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Joubert syndrome, Meckel-Gruber syndrome, and/or nephronophthisis-related ciliopathies (PMID: 17377820, 17397051, 21866095, 23559409, 26092869). ClinVar contains an entry for this variant (Variation ID: 1376). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000494327	SCV000581918	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19508969, 17397051, 31974414, 23352055, 26092869, 23559409, 26729329, 25525159, 17377820, 21866095, 25920555, 28973083, 29891882, 28680603, 28497568, 29146704, 34426522, 31589614)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000723362	SCV001369691	pathogenic	RHYNS syndrome	2019-09-11	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP5.
Revvity Omics, Revvity	RCV000494327	SCV002022352	pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000001443	SCV002026381	pathogenic	Joubert syndrome 6	2021-11-10	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_153704.6:c.2374A>G._x000D_ Criteria applied: PVS1, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298428	SCV002599024	pathogenic	Joubert syndrome and related disorders	2022-09-09	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.622A>T (p.Arg208X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00018 in 251386 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00018 vs 0.0018), allowing no conclusion about variant significance. c.622A>T has been reported in the literature in multiple individuals affected with Joubert Syndrome, Meckel-Gruber syndrome and nephronophthisis-related ciliopathies (e.g. Consugar_2007, Halbritter_2013, Fleming_2017). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490291	SCV002797375	pathogenic	COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11	2022-05-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003242959	SCV003965169	pathogenic	Inborn genetic diseases	2023-06-09	criteria provided, single submitter	clinical testing	The c.622A>T (p.R208*) alteration, located in exon 6 (coding exon 6) of the TMEM67 gene, consists of an A to T substitution at nucleotide position 622. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 208. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.017% (49/282794) total alleles studied. The highest observed frequency was 0.037% (48/129126) of European (non-Finnish) alleles. This variant has been detected in conjunction with other variants in the TMEM67 gene in multiple individuals diagnosed with clinical features associated with TMEM67-related ciliopathies; however, the phase of the two variants is either unspecified or confirmed in trans (opposite chromosome) (Otto, 2009; Khaddour, 2007; Chaki, 2011; Szymanska, 2012; Bachmann-Gagescu, 2015; Summers, 2017; Vogel, 2017; Meng, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000334857	SCV004046148	pathogenic	TMEM67-Related Disorders		criteria provided, single submitter	clinical testing	This variant results in a c.379A>T (p.Arg127Ter) change in an alternate TMEM67 transcript NM_001142301. This gene is also known as MKS3 in the literature (PMID: 17397051). This nonsense variant found in exon 7 of 28 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in the compound heterozygous state in individuals with Joubert Syndrome, Meckel-Gruber syndrome, and nephronophthisis (PMID: 17397051, 21866095, 26092869, 17377820, 23559409). Loss-of-function variation in TMEM67 has been reported in affected individuals in the literature (PMID: 17397051, 21866095, 26092869, 17377820, 23559409). The c.622A>T (p.Arg208Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (49/282,794). Based on the available evidence, the c.622A>T (p.Arg208Ter) variant is classified as Pathogenic.
OMIM	RCV000001442	SCV000021592	pathogenic	Meckel syndrome, type 3	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000001443	SCV000021593	pathogenic	Joubert syndrome 6	2009-10-01	no assertion criteria provided	literature only
OMIM	RCV000723362	SCV000854762	pathogenic	RHYNS syndrome	2009-10-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000494327	SCV001917293	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000494327	SCV001927710	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000494327	SCV001951060	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000494327	SCV001966276	pathogenic	not provided		no assertion criteria provided	clinical testing