ClinVar Genomic variation as it relates to human health
NM_001377265.1(MAPT):c.14G>A (p.Arg5His)
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); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001377265.1(MAPT):c.14G>A (p.Arg5His)
Variation ID: 14261 Accession: VCV000014261.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 45962351 (GRCh38) [ NCBI UCSC ] 17: 44039717 (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 Aug 22, 2016 Feb 7, 2023 Mar 21, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001377265.1:c.14G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001364194.1:p.Arg5His missense NM_001123066.4:c.14G>A NP_001116538.2:p.Arg5His missense NM_001123067.4:c.14G>A NP_001116539.1:p.Arg5His missense NM_001203251.2:c.14G>A NP_001190180.1:p.Arg5His missense NM_001203252.2:c.14G>A NP_001190181.1:p.Arg5His missense NM_001377266.1:c.14G>A NP_001364195.1:p.Arg5His missense NM_001377267.1:c.14G>A NP_001364196.1:p.Arg5His missense NM_001377268.1:c.14G>A NP_001364197.1:p.Arg5His missense NM_005910.6:c.14G>A NP_005901.2:p.Arg5His missense NM_016834.5:c.14G>A NP_058518.1:p.Arg5His missense NM_016835.5:c.14G>A NP_058519.3:p.Arg5His missense NM_016841.5:c.14G>A NP_058525.1:p.Arg5His missense NR_165166.1:n.164G>A non-coding transcript variant NC_000017.11:g.45962351G>A NC_000017.10:g.44039717G>A NG_007398.2:g.72889G>A LRG_660:g.72889G>A LRG_660t1:c.14G>A LRG_660p1:p.Arg5His LRG_660t2:c.14G>A LRG_660p2:p.Arg5His P10636:p.Arg5His - Protein change
- R5H
- Other names
- -
- Canonical SPDI
- NC_000017.11:45962350:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
---|---|---|---|---|---|---|
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. |
|||
MAPT | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh38 GRCh37 |
499 | 631 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Mar 21, 2022 | RCV000015330.32 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000266864.6 |
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. |
|
---|---|---|---|---|---|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
MAPT-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000403475.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
Uncertain significance
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Frontotemporal dementia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001412838.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the MAPT protein (p.Arg5His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the MAPT protein (p.Arg5His). This variant is present in population databases (rs63750959, gnomAD 0.06%). This missense change has been observed in individuals with MAPT-related conditions (PMID: 11921059, 22312439, 26200045, 26601740, 28462717, 28923025, 33580635). ClinVar contains an entry for this variant (Variation ID: 14261). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MAPT function (PMID: 11921059). This variant disrupts the p.Arg5 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 12325083, 18803694, 23043292), which suggests that this may be a clinically significant amino acid residue. 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)
|
|
Pathogenic
(Apr 01, 2002)
|
no assertion criteria provided
Method: literature only
|
DEMENTIA, FRONTOTEMPORAL, WITH PARKINSONISM
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035589.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a patient with late-onset (age 75 years) frontotemporal dementia with parkinsonism (600274), Hayashi et al. (2002) identified a G-to-A transition in exon 1 of … (more)
In a patient with late-onset (age 75 years) frontotemporal dementia with parkinsonism (600274), Hayashi et al. (2002) identified a G-to-A transition in exon 1 of the MAPT gene, resulting in an arg5-to-his (R5H) substitution. Pathologic examination revealed frontotemporal atrophy, neuronal loss, widespread tau-immunoreactive glial cytoplasmic inclusions, and insoluble tau filaments composed of 4-repeat tau. The mutation reduced the ability of tau to promote microtubule assembly and promoted fibril formation in vitro. The patient had an elderly brother with dementia who died at age 86 years. (less)
|
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 |
---|---|---|---|---|
Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan. | Hsu JL | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2021 | PMID: 33580635 |
Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review. | Lin HC | BMC neurology | 2017 | PMID: 28923025 |
Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia. | Che XQ | Current Alzheimer research | 2017 | PMID: 28462717 |
Identification of mutations in Korean patients with amyotrophic lateral sclerosis using multigene panel testing. | Kim HJ | Neurobiology of aging | 2016 | PMID: 26601740 |
[A Pair of Siblings with a rare R5H-Mutation in Exon 1 of the MAPT-Gene]. | Henz S | Fortschritte der Neurologie-Psychiatrie | 2015 | PMID: 26200045 |
FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. | Combs B | Biochemistry | 2012 | PMID: 23043292 |
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 |
Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. | Chang E | Journal of neurochemistry | 2008 | PMID: 18803694 |
An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. | Poorkaj P | Annals of neurology | 2002 | PMID: 12325083 |
Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. | Hayashi S | Annals of neurology | 2002 | PMID: 11921059 |
Text-mined citations for rs63750959 ...
HelpRecord last updated Dec 25, 2023
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.