17-46010389-C-T

Variant names:

• chr17-46010389-C-T
• rs63751273
• NM_001377265.1:c.2078C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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 allele was found at a frequency of 0.00000211 in 1,421,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.38
• Publications: 3383 publications found

Genes affected

MAPT (HGNC:6893): (microtubule associated protein tau) This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]

MAPT Gene-Disease associations (from GenCC):

• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• supranuclear palsy, progressive, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 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, 6 uncertain in NM_001377265.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-46010388-C-T is described in ClinVar as Pathogenic. ClinVar VariationId 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 VariationId is 14245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.2078C>T	p.Pro693Leu	missense_variant	Exon 10 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.2078C>T	p.Pro693Leu	missense_variant	Exon 10 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000535 AC: 1 AN: 186808 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1421918 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703076

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.00 AC: 0 AN: 38606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 38278

South Asian (SAS) AF: 0.00 AC: 0 AN: 80822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090516

Other (OTH) AF: 0.00 AC: 0 AN: 58964

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Pathogenic:6

Jul 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 26, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Apr 24, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro301Leu variant is novel (not in any individuals) in 1kG All. The p.Pro301Leu variant is observed in 3/1,574,190 (0.0002%) alleles from individuals of gnomAD v4 All background in gnomAD v4 All. The p.Pro301Leu variant is novel (not in any individuals) in TopMed (PM2). The gene MAPT has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 3.00. The gene MAPT contains 17 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene (PP2). The p.Pro301Leu missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.902 in MAPT is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Alpha Missense also classifies this variant as pathogenic (PP3). The p.Pro301Leu variant is a missense mutation resulting in an amino acid change which is shared by the previously classified pathogenic variant p.P301L (PS1). The p.Pro301Leu variant is a missense mutation resulting in an amino acid change which occurs at the same amino acid position as the previously classified pathogenic variant p.P301A (PM5).For these reasons, this variant has been classified as Pathogenic. ACMG Criteria - PM2 PP2 PP3 PS1 PM5 -

Jan 22, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

not provided Pathogenic:3 Other:1

Jun 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published 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) -

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VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 10, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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). -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPT: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP3 -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551862:Progressive supranuclear ophthalmoplegia Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Supranuclear palsy, progressive, 1 Pathogenic:1

Jul 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3+PP4+PS3+PS4+PP1_Strong -

MAPT-related disorder Pathogenic:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The 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. 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	34
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;.
PhyloP100		7.4
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63751273; hg19: chr17-44087755;