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NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val) AND Frontotemporal dementia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 6, 2021
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000015315.30

Allele description [Variation Report for NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val)]

NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val)

Gene:
MAPT:microtubule associated protein tau [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val)
HGVS:
  • NC_000017.11:g.45996657G>T
  • NG_007398.2:g.107195G>T
  • NM_001123066.4:c.1820G>T
  • NM_001123067.4:c.728G>T
  • NM_001203251.2:c.728G>T
  • NM_001203252.2:c.815G>T
  • NM_001377265.1:c.1991G>TMANE SELECT
  • NM_001377266.1:c.1793G>T
  • NM_001377267.1:c.728G>T
  • NM_001377268.1:c.641G>T
  • NM_005910.6:c.815G>T
  • NM_016834.5:c.641G>T
  • NM_016835.5:c.1766G>T
  • NM_016841.5:c.641G>T
  • NP_001116538.2:p.Gly607Val
  • NP_001116539.1:p.Gly243Val
  • NP_001190180.1:p.Gly243Val
  • NP_001190181.1:p.Gly272Val
  • NP_001364194.1:p.Gly664Val
  • NP_001364195.1:p.Gly598Val
  • NP_001364196.1:p.Gly243Val
  • NP_001364197.1:p.Gly214Val
  • NP_005901.2:p.Gly272Val
  • NP_058518.1:p.Gly214Val
  • NP_058519.3:p.Gly589Val
  • NP_058525.1:p.Gly214Val
  • LRG_660t1:c.1766G>T
  • LRG_660t2:c.1991G>T
  • LRG_660:g.107195G>T
  • LRG_660p1:p.Gly589Val
  • LRG_660p2:p.Gly664Val
  • NC_000017.10:g.44074023G>T
  • NG_007398.1:g.107237G>T
  • NR_165166.1:n.739G>T
  • P10636:p.Gly589Val
Protein change:
G214V; GLY272VAL
Links:
UniProtKB: P10636#VAR_010345; OMIM: 157140.0002; dbSNP: rs63750376
NCBI 1000 Genomes Browser:
rs63750376
Molecular consequence:
  • NM_001123066.4:c.1820G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001123067.4:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001203251.2:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001203252.2:c.815G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377265.1:c.1991G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377266.1:c.1793G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377267.1:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377268.1:c.641G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005910.6:c.815G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016834.5:c.641G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016835.5:c.1766G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016841.5:c.641G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_165166.1:n.739G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Frontotemporal dementia (FTD1)
Synonyms:
FRONTOTEMPORAL LOBE DEMENTIA; WILHELMSEN-LYNCH DISEASE; Dementia, frontotemporal, with parkinsonism; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0017276; MedGen: C0338451; Orphanet: 282; OMIM: 600274; Human Phenotype Ontology: HP:0002145

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000035574OMIM
no assertion criteria provided
Pathogenic
(May 6, 2021) 		germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Untangling tau-related dementia.

Heutink P.

Hum Mol Genet. 2000 Apr 12;9(6):979-86. Review.

PubMed [citation]
PMID:
10767321

Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms.

Hutton M.

Neurology. 2001 Jun;56(11 Suppl 4):S21-5. Review.

PubMed [citation]
PMID:
11402146
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000035574.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In a second large Dutch kindred with frontotemporal dementia (600274) reported by Heutink et al. (1997) as an example of hereditary Pick disease, Hutton et al. (1998) found a gly272-to-val mutation (G272V) that affected a highly conserved residue within the microtubule-associated domain, encoded by exon 9 of the MAPT gene.

Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including G272V, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 1, 2024