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rs63751273

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong

The NM_001377265.1(MAPT):c.2078C>T(p.Pro693Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P693S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MAPT
NM_001377265.1 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.38

Links

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001377265.1
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-46010388-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14256. Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
?
Variant 17-46010389-C-T is Pathogenic according to our data. Variant chr17-46010389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14245. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010389-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAPTNM_001377265.1 linkuse as main transcriptc.2078C>T p.Pro693Leu missense_variant 10/13 ENST00000262410.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAPTENST00000262410.10 linkuse as main transcriptc.2078C>T p.Pro693Leu missense_variant 10/131 NM_001377265.1 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000211
AC:
3
AN:
1421918
Hom.:
0
AF XY:
0.00000284
AC XY:
2
AN XY:
703076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000275
Gnomad4 OTH exome
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Frontotemporal dementia Pathogenic:5
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 14, 2009- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Klinikum rechts der IsarJan 22, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 09, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 301 of the MAPT protein (p.Pro301Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 9641683, 26220942, 27439681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14245). 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 expected to disrupt MAPT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 9641683, 11756436, 22022446, 22723997, 25592136, 26220942, 26269332, 26519432). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyAug 26, 2019The MAPT c.1907C>T variant is classified as Pathogenic (PS4_Moderate, PS3, PM1, PP3, PP5) NM_005910.5 c.902C>T; p.Pro301Leu has been widely reported in tauopathies such as frontotemporal dementia and alzheimers disease. Mouse models have shown changes in glutamate release and uptake (PMID:25319522) PMID:30528841 - Blauwendraat et al performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center. Identified the variant in one patient who presented clinically with behavioural variant FTD (frontotemporal disorder) and the autopsy showed accumulation of phosphorylated tau protein consistent with Pick's disease. PMID:25319522 - Hunsberger et al 2015. Used a mouse model and measured glutamate levels, glutamate release and uptake/clearance in hippocampus with this variant. The variant resulted in 4-7 fold increase in glutamate release and decreased clearance. This correlated with memory performance in the maze task. concluded that may be a novel way that tau may mediate hyperexcitability (that preceeds alzheimers disease) PMID:2273997 - Orr et al 2012. Used a mouse model and found that mice with the variant display cellular, histological, biochemical and behavioural abnormalities similar to those in human frontotemporal dementia. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenApr 24, 2023- -
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023MAPT: PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, PP3, PP4 -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncMay 10, 2022The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with frontotemporal dementia (FTD) and associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant causes aggregation of tau affecting microtubule assembly (PMID: 10100642, 10214944, 10627302, 10821687, 10932182, 11013246, 11115852, 26269332). -
not provided, no classification providedliterature onlyVIB Department of Molecular Genetics, University of Antwerp-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 14, 2022Published functional studies showed that P301L expression disrupts interaction with the C-terminal half of MAPT and reduces the ability to bind and promote assembly of microtubules (Gunawardana et al., 2015; Hong et al., 1998); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23047372, 26220942, 30279455, 11598310, 29950844, 30528841, 28934750, 23029293, 22561128, 23043292, 21555888, 21294162, 18803694, 25319522, 11081811, 24150109, 11756436, 19304664, 15831501, 23105105, 10218629, 10865093, 23659495, 11102510, 10932182, 18992292, 20097445, 21492964, 24218087, 21849646, 22365544, 22127750, 22022446, 22723997, 14757934, 26269332, 25592136, 25004446, 26146790, 12111297, 25151619, 27439681, 12473404, 9836646, 9641683, 20561037, 27859539, 9736786, 28717674, 29253099, 29568692, 29729423, 26519432, 29105852, 28268100, 31537395, 29282277, 30562452, 32741062, 33061333, 31599329, 10360762, 9811325, 10514099, 33006106, 32843152) -
Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551862:Progressive supranuclear ophthalmoplegia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Supranuclear palsy, progressive, 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 14, 2009- -
MAPT-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact SciencesJun 20, 2023The MAPT c.1907C>T variant is predicted to result in the amino acid substitution p.Pro636Leu. This variant, also reported as p.Pro301Leu using a different transcript NM_005910.6, has been repeatedly documented to be pathogenic in patients with frontotemporal dementia (Blauwendraat et al. 2018. PubMed ID: 30528841;Borrego-Écija et al. 2017. PubMed ID: 28934750; Dumanchin et al. 1998. PubMed ID: 9736786; Gatto et al. 2017. PubMed ID: 28268100). The c.1907C>T variant has also been interpreted as pathogenic by other labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14245/). This variant is reported in 0.0013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-44087755-C-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
29
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.;.;.;.;.;.;D;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;.;.;.;.
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M;.;.;.;.;.;.;M;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.7
D;D;D;D;D;D;D;.;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;.;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D
Vest4
0.85
MutPred
0.89
Gain of catalytic residue at P618 (P = 0.024);.;.;.;.;.;.;Gain of catalytic residue at P618 (P = 0.024);.;
MVP
1.0
MPC
2.0
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.88
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs63751273; hg19: chr17-44087755; API