VCV000001376.35 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1376 Accession: VCV000001376.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.1 8: 93765617 (GRCh38) [ NCBI UCSC ] 8: 94777845 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Oct 8, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153704.6:c.622A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_714915.3:p.Arg208Ter	nonsense
NM_001142301.1:c.379A>T	NP_001135773.1:p.Arg127Ter	nonsense
NR_024522.2:n.643A>T		non-coding transcript variant
NC_000008.11:g.93765617A>T
NC_000008.10:g.94777845A>T
NG_009190.1:g.15774A>T
LRG_688:g.15774A>T
LRG_688t1:c.622A>T	LRG_688p1:p.Arg208Ter
LRG_688t2:c.379A>T	LRG_688p2:p.Arg127Ter

... more HGVS ... less HGVS

Protein change

R208*, R127*

Other names

Canonical SPDI

NC_000008.11:93765616:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00014

The Genome Aggregation Database (gnomAD), exomes 0.00018

Trans-Omics for Precision Medicine (TOPMed) 0.00022

The Genome Aggregation Database (gnomAD) 0.00026

Links

ClinGen: CA114963 OMIM: 609884.0011 dbSNP: rs137853108 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TMEM67		-	-	GRCh38 GRCh37	1189	1233

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Joubert syndrome 6	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 10, 2021	RCV000001443.14
Meckel syndrome, type 3	Pathogenic (1)	no assertion criteria provided	Oct 1, 2009	RCV000001442.7
Familial aplasia of the vermis Meckel-Gruber syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 19, 2024	RCV000468558.8
TMEM67-related disorder	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 27, 2017	RCV000334857.8
RHYNS syndrome	Pathogenic (2)	criteria provided, single submitter	Sep 11, 2019	RCV000723362.5
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 13, 2022	RCV000494327.18
Joubert syndrome and related disorders	Pathogenic (1)	criteria provided, single submitter	Sep 9, 2022	RCV002298428.1
Bardet-Biedl syndrome 14 COACH syndrome 1 Joubert syndrome 6 Meckel syndrome, type 3 Nephronophthisis 11 RHYNS syndrome	Pathogenic (1)	criteria provided, single submitter	May 26, 2022	RCV002490291.1
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 9, 2023	RCV003242959.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 16, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 6 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000249165.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Jul 25, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331571.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 17397051‚ 21866095‚ 25920555 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TMEM67 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	TMEM67-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000475327.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (4) PubMed: 17377820‚ 23559409‚ 17397051‚ 19508969 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 6 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002026381.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021	Comment: This variant was identified as compound heterozygous with NM_153704.6:c.2374A>G._x000D_ Criteria applied: PVS1, PS4
Pathogenic (Sep 09, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Joubert syndrome and related disorders Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002599024.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (3) PubMed: 17377820‚ 29146704‚ 23559409 Comment: 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 … (more) 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. (less)
Pathogenic (May 13, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000581918.6 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TMEM67-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046148.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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: … (more) 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. (less)
Pathogenic (May 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022352.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial aplasia of the vermis Meckel-Gruber syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000552811.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20232449‚ 23559409‚ 17377820‚ 17397051‚ 21866095‚ 26092869 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 23, 2015)	criteria provided, single submitter (Bachmann-Gagescu et al. (J Med Genet. 2015)) Method: research	Joubert syndrome 6 Affected status: yes Allele origin: unknown	UW Hindbrain Malformation Research Program, University of Washington Additional submitter: University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000256498.1 First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015	Publications: PubMed (1) PubMed: 26092869
Pathogenic (Sep 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RHYNS syndrome Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369691.2 First in ClinVar: Jul 05, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP5.
Pathogenic (May 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	COACH syndrome 1 RHYNS syndrome Meckel syndrome, type 3 Joubert syndrome 6 Nephronophthisis 11 Bardet-Biedl syndrome 14 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002797375.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jun 09, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003965169.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 17397051‚ 19508969‚ 21866095‚ 23351400‚ 26092869‚ 28497568‚ 28680603‚ 28973083 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 01, 2009)	no assertion criteria provided Method: literature only	MECKEL SYNDROME, TYPE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021592.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 17377820‚ 19508969‚ 9375913‚ 29891882 Comment on evidence: Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion … (more) Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene. Joubert Syndrome 6 In a German patient with Joubert syndrome-6 (JBTS6; 610688), Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (609884.0013). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed. RHYNS Syndrome In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; 609884.0026) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9). (less)
Pathogenic (Oct 01, 2009)	no assertion criteria provided Method: literature only	JOUBERT SYNDROME 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021593.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 17377820‚ 19508969‚ 9375913‚ 29891882 Comment on evidence: Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion … (more) Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene. Joubert Syndrome 6 In a German patient with Joubert syndrome-6 (JBTS6; 610688), Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (609884.0013). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed. RHYNS Syndrome In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; 609884.0026) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9). (less)
Pathogenic (Oct 01, 2009)	no assertion criteria provided Method: literature only	RHYNS SYNDROME (1 patient) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000854762.2 First in ClinVar: Dec 10, 2018 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 17377820‚ 19508969‚ 9375913‚ 29891882 Comment on evidence: Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion … (more) Meckel Syndrome In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene. Joubert Syndrome 6 In a German patient with Joubert syndrome-6 (JBTS6; 610688), Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (609884.0013). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed. RHYNS Syndrome In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; 609884.0026) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917293.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927710.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951060.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (May 01, 2024)	no assertion criteria provided Method: clinical testing	TMEM67-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345435.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The TMEM67 c.622A>T variant is predicted to result in premature protein termination (p.Arg208). This variant has been reported to be causative for Meckel syndrome, Joubert … (more) The TMEM67 c.622A>T variant is predicted to result in premature protein termination (p.Arg208). This variant has been reported to be causative for Meckel syndrome, Joubert syndrome, and other related disorders (Khaddour et al. 2007. PubMed ID: 17397051; Table S8, Chaki et al. 2011. PubMed ID: 21866095; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Table S2, Summers et al. 2017. PubMed ID: 28497568). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TMEM67 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966276.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
click to load more click to collapse

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The TMEM67 c.622A>T variant is predicted to result in premature protein termination (p.Arg208*). This variant has been reported to be causative for Meckel syndrome, Joubert syndrome, and other related disorders (Khaddour et al. 2007. PubMed ID: 17397051; Table S8, Chaki et al. 2011. PubMed ID: 21866095; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Table S2, Summers et al. 2017. PubMed ID: 28497568). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TMEM67 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.	Brancati F	European journal of human genetics : EJHG	2018	PMID: 29891882
Prospective Evaluation of Kidney Disease in Joubert Syndrome.	Fleming LR	Clinical journal of the American Society of Nephrology : CJASN	2017	PMID: 29146704
Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.	Meng L	JAMA pediatrics	2017	PMID: 28973083
Isolated congenital hepatic fibrosis associated with TMEM67 mutations: report of a new genotype-phenotype relationship.	Vogel I	Clinical case reports	2017	PMID: 28680603
Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center.	Summers AC	American journal of medical genetics. Part A	2017	PMID: 28497568
Joubert syndrome: genotyping a Northern European patient cohort.	Kroes HY	European journal of human genetics : EJHG	2016	PMID: 25920555
Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.	Bachmann-Gagescu R	Journal of medical genetics	2015	PMID: 26092869
Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.	Halbritter J	Human genetics	2013	PMID: 23559409
Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies.	Szymanska K	Cilia	2012	PMID: 23351400
Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies.	Chaki M	Kidney international	2011	PMID: 21866095
Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies.	Iannicelli M	Human mutation	2010	PMID: 20232449
Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).	Otto EA	Journal of medical genetics	2009	PMID: 19508969
Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.	Khaddour R	Human mutation	2007	PMID: 17397051
Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.	Consugar MB	Human genetics	2007	PMID: 17377820
Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?	Di Rocco M	American journal of medical genetics	1997	PMID: 9375913
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TMEM67	-	-	-	-
click to load more click to collapse

Text-mined citations for rs137853108 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853108 ...