ClinVar Genomic variation as it relates to human health
NM_001377265.1(MAPT):c.1891G>A (p.Ala631Thr)
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.
Uncertain significance(1); Benign(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001377265.1(MAPT):c.1891G>A (p.Ala631Thr)
Variation ID: 98208 Accession: VCV000098208.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 45996557 (GRCh38) [ NCBI UCSC ] 17: 44073923 (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 Feb 20, 2014 Apr 15, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001377265.1:c.1891G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001364194.1:p.Ala631Thr missense NM_001123066.3:c.1720G>A NM_001123066.4:c.1720G>A NP_001116538.2:p.Ala574Thr missense NM_001123067.4:c.628G>A NP_001116539.1:p.Ala210Thr missense NM_001203251.2:c.628G>A NP_001190180.1:p.Ala210Thr missense NM_001203252.2:c.715G>A NP_001190181.1:p.Ala239Thr missense NM_001377266.1:c.1693G>A NP_001364195.1:p.Ala565Thr missense NM_001377267.1:c.628G>A NP_001364196.1:p.Ala210Thr missense NM_001377268.1:c.541G>A NP_001364197.1:p.Ala181Thr missense NM_005910.6:c.715G>A NP_005901.2:p.Ala239Thr missense NM_016834.5:c.541G>A NP_058518.1:p.Ala181Thr missense NM_016835.5:c.1666G>A NP_058519.3:p.Ala556Thr missense NM_016841.5:c.541G>A NP_058525.1:p.Ala181Thr missense NR_165166.1:n.639G>A non-coding transcript variant NC_000017.11:g.45996557G>A NC_000017.10:g.44073923G>A NG_007398.2:g.107095G>A LRG_660:g.107095G>A LRG_660t1:c.1666G>A LRG_660p1:p.Ala556Thr LRG_660t2:c.1891G>A LRG_660p2:p.Ala631Thr - Protein change
- A556T, A239T, A574T, A181T, A210T, A565T, A631T
- Other names
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- Canonical SPDI
- NC_000017.11:45996556: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00063
The Genome Aggregation Database (gnomAD) 0.00085
Trans-Omics for Precision Medicine (TOPMed) 0.00097
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00138
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
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. |
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MAPT | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh38 GRCh37 |
499 | 630 |
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. |
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Benign (3) |
criteria provided, single submitter
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Jan 30, 2019 | RCV000084513.6 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000325065.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV000805364.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV003993800.1 | |
MAPT-related disorder
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Likely benign (1) |
criteria provided, single submitter
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May 26, 2023 | RCV003935077.1 |
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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Benign
(Jan 30, 2019)
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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: SCV001837260.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 17071927, 25466404, 23053136)
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Uncertain significance
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Frontotemporal dementia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000945317.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the MAPT protein (p.Ala239Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the MAPT protein (p.Ala239Thr). This variant is present in population databases (rs63750096, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Alzheimer's disease, frontotemporal dementia, and/or Parkinson disease (PMID: 11912108, 22312439, 23053136, 25466404, 27094865). ClinVar contains an entry for this variant (Variation ID: 98208). 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 not expected to disrupt MAPT protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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MAPT-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004751078.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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MAPT-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000403485.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Likely benign
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive supranuclear palsy-parkinsonism syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812358.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551959.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MAPT p.Ala239Thr variant was identified in 5/91 individuals with late-onset Parkinson's Disease (age of onset 62-87) and in 1/96 control individuals (Petersen_2015_PMID:25466404). The variant … (more)
The MAPT p.Ala239Thr variant was identified in 5/91 individuals with late-onset Parkinson's Disease (age of onset 62-87) and in 1/96 control individuals (Petersen_2015_PMID:25466404). The variant was also identified in a woman with frontotemporal lobar degeneration but was not found in her two brothers with amyotrophic lateral sclerosis; the woman and her brothers also all carried an intronic GGGGCC hexanucleotide repeat expansion in C9ORF72 (King_2013_PMID:23053136). A British patient with frontotemporal dementia with a tau‚Äênegative, microvacuolar‚Äêtype histology was also reported to carry the MAPT p.A239T variant (Pickering-Brown_2002_PMID:11912108). The p.A239T variant was also identified in 4/439 late-onset Alzheimer disease (AD) families, 4/1,806 sporadic AD cases and 4/1,346 elderly controls (Cruchaga_2012_PMID:22312439). The variant was identified in dbSNP (ID: rs63750096), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae and as likely benign by Illumina). The variant was not identified in databases. The variant was identified in control databases in 177 of 279944 chromosomes at a frequency of 0.0006323 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 153 of 127156 chromosomes (freq: 0.001203), African in 14 of 24686 chromosomes (freq: 0.000567), European (Finnish) in 4 of 24990 chromosomes (freq: 0.00016), Latino in 5 of 35350 chromosomes (freq: 0.000141) and Other in 1 of 7152 chromosomes (freq: 0.00014), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Ala239 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116649.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_316
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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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Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. | Benitez BA | Molecular neurodegeneration | 2016 | PMID: 27094865 |
Parkinson's disease, genetic variability and the Faroe Islands. | Petersen MS | Parkinsonism & related disorders | 2015 | PMID: 25466404 |
Mixed tau, TDP-43 and p62 pathology in FTLD associated with a C9ORF72 repeat expansion and p.Ala239Thr MAPT (tau) variant. | King A | Acta neuropathologica | 2013 | PMID: 23053136 |
Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. | Cruchaga C | PloS one | 2012 | PMID: 22312439 |
Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. | Pickering-Brown SM | Brain : a journal of neurology | 2002 | PMID: 11912108 |
Text-mined citations for rs63750096 ...
HelpRecord last updated May 19, 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.