Submissions for variant NM_001377265.1(MAPT):c.2078C>T (p.Pro693Leu)

dbSNP: rs63751273

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000084527	SCV000614049	pathogenic	not provided	2022-05-10	criteria provided, single submitter	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).
Invitae	RCV000015313	SCV000813769	pathogenic	Frontotemporal dementia	2021-11-27	criteria provided, single submitter	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). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763405	SCV000894132	pathogenic	Frontotemporal dementia; Parkinson disease, late-onset; Progressive supranuclear palsy-parkinsonism syndrome; Pick disease; Progressive supranuclear ophthalmoplegia	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Klinikum rechts der Isar	RCV000015313	SCV001150159	pathogenic	Frontotemporal dementia	2018-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000084527	SCV001961704	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000084527	SCV002526518	pathogenic	not provided	2022-06-14	criteria provided, single submitter	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)
Genetics and Molecular Pathology, SA Pathology	RCV000015313	SCV002556557	pathogenic	Frontotemporal dementia	2019-08-26	criteria provided, single submitter	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.
OMIM	RCV000015313	SCV000035572	pathogenic	Frontotemporal dementia	2009-07-14	no assertion criteria provided	literature only
OMIM	RCV000015314	SCV000035573	pathogenic	Progressive supranuclear ophthalmoplegia	2009-07-14	no assertion criteria provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084527	SCV000116663	not provided	not provided		no assertion provided	not provided