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NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
10 (Most recent: Sep 2, 2021)
Last evaluated:
Jun 30, 2021
Accession:
VCV000001378.11
Variation ID:
1378
Description:
single nucleotide variant
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NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr)

Allele ID
16417
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
8q22.1
Genomic location
8: 93808898 (GRCh38) GRCh38 UCSC
8: 94821126 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_153704.5:c.2498T>C NP_714915.3:p.Ile833Thr missense
NC_000008.10:g.94821126T>C
NC_000008.11:g.93808898T>C
... more HGVS
Protein change
I833T, I752T
Other names
-
Canonical SPDI
NC_000008.11:93808897:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00007
Links
OMIM: 609884.0013
dbSNP: rs267607119
ClinGen: CA210657
UniProtKB: Q5HYA8#VAR_063801
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 3 criteria provided, multiple submitters, no conflicts Dec 3, 2018 RCV000001446.7
Pathogenic 1 criteria provided, single submitter Nov 20, 2019 RCV000821785.2
Pathogenic 1 criteria provided, single submitter Jun 30, 2021 RCV001536092.1
Pathogenic 3 criteria provided, single submitter Dec 1, 2020 RCV001310635.3
Pathogenic 1 no assertion criteria provided Jul 1, 2011 RCV000001445.5
Pathogenic 1 no assertion criteria provided May 23, 2018 RCV000995902.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TMEM67 - - GRCh38
GRCh37
340 372

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Dec 03, 2018)
criteria provided, single submitter
Method: research
Joubert syndrome 6
(Autosomal recessive inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001164447.1
Submitted: (Oct 03, 2019)
Evidence details
Publications
PubMed (4)
Comment:
The heterozygous p.Ile833Thr variant in TMEM67 was identified by our study in the compound heterozygous state, with a VUS, in one individual with Joubert syndrome. … (more)
Pathogenic
(Dec 01, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001500515.2
Submitted: (Jul 04, 2021)
Evidence details
Pathogenic
(Feb 23, 2015)
criteria provided, single submitter
Method: research
Joubert syndrome 6
Allele origin: unknown
UW Hindbrain Malformation Research Program,University of Washington
Additional submitter:
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000256494.1
Submitted: (Sep 16, 2015)
Evidence details
Publications
PubMed (1)
Pathogenic
(Nov 20, 2019)
criteria provided, single submitter
Method: clinical testing
Joubert syndrome
Meckel-Gruber syndrome
Allele origin: germline
Invitae
Accession: SCV000962554.2
Submitted: (Feb 06, 2020)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces isoleucine with threonine at codon 833 of the TMEM67 protein (p.Ile833Thr). The isoleucine residue is moderately conserved and there is a … (more)
Pathogenic
(Jun 30, 2021)
criteria provided, single submitter
Method: clinical testing
Joubert syndrome with hepatic defect
RHYNS syndrome
Meckel syndrome, type 3
Joubert syndrome 6
Nephronophthisis 11
Bardet-Biedl syndrome 14
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV001752801.1
Submitted: (Jul 09, 2021)
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
Evidence details
Pathogenic
(Jul 01, 2011)
no assertion criteria provided
Method: literature only
JOUBERT SYNDROME 6
Allele origin: germline
OMIM
Accession: SCV000021596.4
Submitted: (Aug 09, 2016)
Evidence details
Publications
PubMed (5)
Pathogenic
(May 23, 2018)
no assertion criteria provided
Method: clinical testing
Meckel syndrome, type 3
(Autosomal recessive inheritance)
Allele origin: paternal
Institute of Human Genetics, Klinikum rechts der Isar
Accession: SCV001150294.1
Submitted: (Jan 21, 2020)
Evidence details
Pathogenic
(Sep 23, 2019)
no assertion criteria provided
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001820879.1
Submitted: (Sep 01, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Pathogenic
(Jul 01, 2011)
no assertion criteria provided
Method: literature only
COACH SYNDROME
Allele origin: germline
OMIM
Accession: SCV000021595.4
Submitted: (Aug 09, 2016)
Evidence details
Publications
PubMed (5)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740236.3
Submitted: (Sep 02, 2021)
Evidence details

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
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
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: a model for untangling recessive disorders with extreme genetic heterogeneity. Bachmann-Gagescu R Journal of medical genetics 2015 PMID: 26092869
Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Chaki M Kidney international 2011 PMID: 21866095
Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. Dafinger C The Journal of clinical investigation 2011 PMID: 21633164
Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). Doherty D Journal of medical genetics 2010 PMID: 19574260
Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). Otto EA Journal of medical genetics 2009 PMID: 19508969
MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement. Brancati F Human mutation 2009 PMID: 19058225
Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. Verloes A American journal of medical genetics 1989 PMID: 2929661

Text-mined citations for rs267607119...

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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 Sep 07, 2021