rs63751273

chr17-46010389-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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:11 O:1
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 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, 5 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-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075676.Status of the report is criteria_provided_single_submitter, 1 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
MAPT	NM_001377265.1	c.2078C>T	p.Pro693Leu	missense_variant	10/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2078C>T	p.Pro693Leu	missense_variant	10/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

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

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 26, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 14, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	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). 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. -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MAPT: PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2022	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). -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Supranuclear palsy, progressive, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 14, 2009

- -

MAPT-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2023

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 (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	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;.
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

Other links and lift over

dbSNP: rs63751273; hg19: chr17-44087755;