NM_001377265.1(MAPT):c.14G>A (p.Arg5His) AND Frontotemporal dementia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 21, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000015330.33

Allele description [Variation Report for NM_001377265.1(MAPT):c.14G>A (p.Arg5His)]

NM_001377265.1(MAPT):c.14G>A (p.Arg5His)

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.14G>A (p.Arg5His)

HGVS:

NC_000017.11:g.45962351G>A
NG_007398.2:g.72889G>A
NM_001123066.4:c.14G>A
NM_001123067.4:c.14G>A
NM_001203251.2:c.14G>A
NM_001203252.2:c.14G>A
NM_001377265.1:c.14G>AMANE SELECT
NM_001377266.1:c.14G>A
NM_001377267.1:c.14G>A
NM_001377268.1:c.14G>A
NM_005910.6:c.14G>A
NM_016834.5:c.14G>A
NM_016835.5:c.14G>A
NM_016841.5:c.14G>A
NP_001116538.2:p.Arg5His
NP_001116539.1:p.Arg5His
NP_001190180.1:p.Arg5His
NP_001190181.1:p.Arg5His
NP_001364194.1:p.Arg5His
NP_001364195.1:p.Arg5His
NP_001364196.1:p.Arg5His
NP_001364197.1:p.Arg5His
NP_005901.2:p.Arg5His
NP_005901.2:p.Arg5His
NP_058518.1:p.Arg5His
NP_058519.3:p.Arg5His
NP_058525.1:p.Arg5His
LRG_660t1:c.14G>A
LRG_660t2:c.14G>A
LRG_660:g.72889G>A
LRG_660p1:p.Arg5His
LRG_660p2:p.Arg5His
NC_000017.10:g.44039717G>A
NG_007398.1:g.72930G>A
NM_005910.5:c.14G>A
NR_165166.1:n.164G>A
P10636:p.Arg5His

Protein change:

R5H; ARG5HIS

Links:

UniProtKB: P10636#VAR_019660; OMIM: 157140.0017; dbSNP: rs63750959

NCBI 1000 Genomes Browser:

rs63750959

Molecular consequence:

NM_001123066.4:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001123067.4:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001203251.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001203252.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377265.1:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377266.1:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377267.1:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377268.1:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005910.6:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016834.5:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016835.5:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016841.5:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_165166.1:n.164G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035589	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001412838	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 21, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 22312439, 26200045, 26601740, 28462717, 28923025, 33580635, 11921059, 12325083, 18803694, 23043292, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035589

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 2002)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001412838

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 21, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.

Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM; NIA-LOAD/NCRAD Family Study Consortium..

PLoS One. 2012;7(2):e31039. doi: 10.1371/journal.pone.0031039. Epub 2012 Feb 1. Erratum in: PLoS One. 2012;7(5): doi/10.1371/annotation/c92e16da-7733-421d-b063-1db19488daa6. Haller, Gabe [added]..

PubMed [citation]

PMID:: 22312439
PMCID:: PMC3270040

[A Pair of Siblings with a rare R5H-Mutation in Exon 1 of the MAPT-Gene].

Henz S, Ackl N, Knels C, Rominger A, Flatz W, Teipel S, Huppertz HJ, Roeber S, Neumann M, Danek A.

Fortschr Neurol Psychiatr. 2015 Jul;83(7):397-401. doi: 10.1055/s-0035-1553236. Epub 2015 Jul 22. German.

PubMed [citation]

PMID:: 26200045

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000035589.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001412838.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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