ClinVar Genomic variation as it relates to human health
NM_153704.6(TMEM67):c.1645C>T (p.Arg549Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153704.6(TMEM67):c.1645C>T (p.Arg549Cys)
Variation ID: 530903 Accession: VCV000530903.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q22.1 8: 93793267 (GRCh38) [ NCBI UCSC ] 8: 94805495 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 28, 2018 Feb 28, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153704.6:c.1645C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_714915.3:p.Arg549Cys missense NM_001142301.1:c.1402C>T NP_001135773.1:p.Arg468Cys missense NR_024522.2:n.1666C>T non-coding transcript variant NC_000008.11:g.93793267C>T NC_000008.10:g.94805495C>T NG_009190.1:g.43424C>T LRG_688:g.43424C>T LRG_688t1:c.1645C>T LRG_688p1:p.Arg549Cys LRG_688t2:c.1402C>T LRG_688p2:p.Arg468Cys - Protein change
- R468C, R549C
- Other names
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- Canonical SPDI
- NC_000008.11:93793266:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00009
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 | ||
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HI score
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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
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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. |
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TMEM67 | - | - |
GRCh38 GRCh37 |
1153 | 1197 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2024 | RCV000636959.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2022 | RCV001591420.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV001779030.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003338698.3 |
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. |
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Pathogenic
(Oct 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome and related disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015091.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: TMEM67 c.1645C>T (p.Arg549Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: TMEM67 c.1645C>T (p.Arg549Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251456 control chromosomes (gnomAD). This frequency is lower than the maximum expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.1645C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Hopp_2011, Szymanska_2012, Zhang_2015), including segregation evidence in one of the reported families (Zhang_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001816479.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrated that mouse embryonic fibroblasts homozygous for the R549C variant failed to rescue basal responses to Wnt3a (Abdelhamed et al., 2015); In … (more)
Published functional studies demonstrated that mouse embryonic fibroblasts homozygous for the R549C variant failed to rescue basal responses to Wnt3a (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: 24039893, 21493627, 26035863, 26191240, 23351400, 29304564) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Meckel syndrome, type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047047.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant p.R549C in TMEM67 (NM_153704.6) has been previously reported as homozygous or in combination with another TMEM67 variant in individuals affected with Meckel … (more)
The missense variant p.R549C in TMEM67 (NM_153704.6) has been previously reported as homozygous or in combination with another TMEM67 variant in individuals affected with Meckel syndrome ( Hopp et al, 2011). The p.R549C variant is observed in 4/18,394 (0.0217%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Experimental studies have shown that this missense change is unable to rescue de-regulated Wnt/beta-catenin signaling that is present in a null knockout mouse model (Abdelhamed et al, 2015). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R549C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1645 in TMEM67 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. No significant variants in gene TMEM67 were detected in the spouse. (less)
Clinical Features:
Seizure (present)
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Pathogenic
(Jan 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000758407.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 549 of the TMEM67 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 549 of the TMEM67 protein (p.Arg549Cys). This variant is present in population databases (rs747025617, gnomAD 0.02%). This missense change has been observed in individuals with Meckel syndrome (PMID: 21493627, 23351400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 530903). 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: 26035863). For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report. | Bui TPH | BMC medical genetics | 2020 | PMID: 32000717 |
A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China. | Zhang M | International journal of clinical and experimental pathology | 2015 | PMID: 26191240 |
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway. | Abdelhamed ZA | Disease models & mechanisms | 2015 | PMID: 26035863 |
Preimplantation genetic diagnosis for a Chinese family with autosomal recessive Meckel-Gruber syndrome type 3 (MKS3). | Lu Y | PloS one | 2013 | PMID: 24039893 |
Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. | Szymanska K | Cilia | 2012 | PMID: 23351400 |
B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. | Hopp K | Human molecular genetics | 2011 | PMID: 21493627 |
Text-mined citations for rs747025617 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.