ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp)

gnomAD frequency: 0.00002  dbSNP: rs63750424
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000084554 SCV000614041 pathogenic not provided 2014-11-26 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002476970 SCV000894133 pathogenic Frontotemporal dementia; Parkinson disease, late-onset; Progressive supranuclear palsy-parkinsonism syndrome; Pick disease; Supranuclear palsy, progressive, 1 2022-03-15 criteria provided, single submitter clinical testing
Invitae RCV000015316 SCV001223220 pathogenic Frontotemporal dementia 2023-04-01 criteria provided, single submitter clinical testing This missense change has been observed in individuals with behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease, and/or mixed dementia with parkinsonism (PMID: 9382467, 9641683, 11117542, 11889249, 23383383, 23727082, 25942996, 26028272). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750424, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the MAPT protein (p.Arg406Trp). ClinVar contains an entry for this variant (Variation ID: 14247). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MAPT function (PMID: 10797541, 11102510, 11756436, 19304664, 21339331, 24150109). 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 not expected to disrupt MAPT protein function.
GeneDx RCV000084554 SCV001781734 pathogenic not provided 2021-09-02 criteria provided, single submitter clinical testing Published functional studies demonstrate that R406W cells show a decreased level of phosphorylation and are unable to bind to microtubules resulting in accumulation in the cytoplasm (Perez et al., 2000; Delobel et al., 2002).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33061333, 30924900, 30562452, 31836585, 31127772, 29370822, 30279455, 23727082, 20683187, 18587238, 10514099, 14517953, 9641683, 18284428, 11889249, 12368474, 11278002, 29253099, 25942996, 26734663, 25377499, 26028272, 26581847, 20377816, 22787795, 21849646, 18992292, 11102510, 21339331, 23105105, 19304664, 11756436, 23338682, 20634584, 24150109, 10820221, 18803694, 22368988, 23383383)
CeGaT Center for Human Genetics Tuebingen RCV000084554 SCV002063631 pathogenic not provided 2021-12-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000015316 SCV004175704 pathogenic Frontotemporal dementia 2023-12-12 criteria provided, single submitter clinical testing
OMIM RCV000015316 SCV000035575 pathogenic Frontotemporal dementia 2003-11-01 no assertion criteria provided literature only
VIB Department of Molecular Genetics, University of Antwerp RCV000084554 SCV000116690 not provided not provided no assertion provided not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000084554 SCV001977751 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000084554 SCV001980402 pathogenic not provided no assertion criteria provided clinical testing

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