Total submissions: 12
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 | 2024-01-09 | 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 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. |
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 Munich, |
RCV000015313 | SCV001150159 | pathogenic | Frontotemporal dementia | 2018-01-22 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000084527 | SCV001961704 | pathogenic | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | MAPT: PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, PP3, PP4 |
Gene |
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, |
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. |
Institute of Medical Genetics and Applied Genomics, |
RCV000015313 | SCV003918898 | pathogenic | Frontotemporal dementia | 2023-04-24 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
RCV003407335 | SCV004115150 | pathogenic | MAPT-related condition | 2023-06-20 | criteria provided, single submitter | 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 (http://gnomad.broadinstitute.org/variant/17-44087755-C-T). This variant is interpreted as pathogenic. |
OMIM | RCV000015313 | SCV000035572 | pathogenic | Frontotemporal dementia | 2009-07-14 | no assertion criteria provided | literature only | |
OMIM | RCV002508757 | SCV000035573 | pathogenic | Supranuclear palsy, progressive, 1 | 2009-07-14 | no assertion criteria provided | literature only | |
VIB Department of Molecular Genetics, |
RCV000084527 | SCV000116663 | not provided | not provided | no assertion provided | not provided |