ClinVar Genomic variation as it relates to human health
NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn)
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_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn)
Variation ID: 523236 Accession: VCV000523236.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p21.3 7: 12231904 (GRCh38) [ NCBI UCSC ] 7: 12271530 (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 13, 2018 Oct 13, 2024 Sep 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001134232.2:c.754G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127704.1:p.Asp252Asn missense NM_018374.4:c.754G>A NP_060844.2:p.Asp252Asn missense NC_000007.14:g.12231904G>A NC_000007.13:g.12271530G>A - Protein change
- D252N
- Other names
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- Canonical SPDI
- NC_000007.14:12231903:G:A
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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
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The frequency of the allele represented by this VCV record.
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- Links
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
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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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TMEM106B | - | - |
GRCh38 GRCh37 |
101 | 141 |
Conditions - Germline
Condition
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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. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2024 | RCV000626490.9 | |
Pathogenic (3) |
criteria provided, single submitter
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Oct 9, 2023 | RCV001561829.9 |
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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Likely pathogenic
(Oct 15, 2018)
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criteria provided, single submitter
Method: curation
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Leukodystrophy, hypomyelinating, 16
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000883307.1
First in ClinVar: May 13, 2018 Last updated: May 13, 2018 |
Comment:
This variant is interpreted as Likely Pathogenic, for Leukodystrophy, hypomyelinating, 16, autosomal dominant. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but … (more)
This variant is interpreted as Likely Pathogenic, for Leukodystrophy, hypomyelinating, 16, autosomal dominant. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29444210). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29444210,29186371). (less)
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Pathogenic
(May 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 16
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520381.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 16
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976681.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2, PM6, PP3, PP5
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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 16
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061269.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.754G>A;p.(Asp252Asn) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 523236; PMID: 29186371; 29194508; 32572497; 32595021) … (more)
The c.754G>A;p.(Asp252Asn) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 523236; PMID: 29186371; 29194508; 32572497; 32595021) - PS4.The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 29186371; 29444210) - PS2.The variant is located in a mutational hot spot and/or critical and well-established functional domain(DUF1356 domain; PMID:29444210) - PM1. This variant is not present in population databases (rs1554310600, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: research
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Leukodystrophy, hypomyelinating, 16
(Sporadic)
Affected status: yes
Allele origin:
de novo
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MyeliNeuroGene Lab, McGill University Health Center Research Institute
Accession: SCV002820973.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 09, 2023)
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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: SCV001784498.2
First in ClinVar: Aug 14, 2021 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 29186371, 29444210, 32595021, 32543692, 37077564, 32572497, 36950148, 36046422, 33597727) (less)
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Pathogenic
(Sep 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy, hypomyelinating, 16
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374359.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
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Pathogenic
(May 08, 2018)
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no assertion criteria provided
Method: literature only
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LEUKODYSTROPHY, HYPOMYELINATING, 16
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000747191.1
First in ClinVar: May 13, 2018 Last updated: May 13, 2018 |
Comment on evidence:
In 4 unrelated patients with hypomyelinating leukodystrophy-16 (HLD16; 617964) Simons et al. (2017) identified a heterozygous c.754G-A transition (c.754G-A, NM_001134232) in exon 8 of the … (more)
In 4 unrelated patients with hypomyelinating leukodystrophy-16 (HLD16; 617964) Simons et al. (2017) identified a heterozygous c.754G-A transition (c.754G-A, NM_001134232) in exon 8 of the TMEM106B gene, resulting in an asp252-to-asn (D252N) substitution at a highly conserved residue in the intraluminal part of the protein. The mutation, which was identified by trio-based whole-exome or whole-genome sequencing, was not found in the dbSNP, ExAC, or gnomAD databases. The mutation occurred de novo in 3 patients, but the mildly affected father of 1 of the patients (patient 3) was mosaic for the mutation. Functional studies of the variant and studies of patient cells were not performed. Yan et al. (2018) identified a de novo heterozygous D252N mutation in the TMEM106B gene in a 3-year-old girl of Chinese descent with HLD16. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but Yan et al. (2018) noted that the mutation occurred at a CpG dinucleotide, suggesting that it is a recurrent mutation due to a hotspot within the gene. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809210.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001958284.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Leukodystrophy, hypomyelinating, 16
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927863.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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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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A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay. | Ikemoto S | Brain & development | 2020 | PMID: 32595021 |
A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination. | Feng T | Brain : a journal of neurology | 2020 | PMID: 32572497 |
The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot. | Yan H | Brain : a journal of neurology | 2018 | PMID: 29444210 |
TMEM106B and myelination: rare leukodystrophy families reveal unexpected connections. | Zhou X | Brain : a journal of neurology | 2017 | PMID: 29194508 |
A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. | Simons C | Brain : a journal of neurology | 2017 | PMID: 29186371 |
Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America. | Santamaria R | Clinical genetics | 2007 | PMID: 17309651 |
Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. | Santamaria R | Human mutation | 2006 | PMID: 16941474 |
beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement. | Morrone A | Human mutation | 2000 | PMID: 10737981 |
Six novel beta-galactosidase gene mutations in Brazilian patients with GM1-gangliosidosis. | Silva CM | Human mutation | 1999 | PMID: 10338095 |
Text-mined citations for rs1554310600 ...
HelpRecord last updated Oct 20, 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.