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: 9
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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 RCV000763406 SCV000894133 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
Invitae RCV000015316 SCV001223220 pathogenic Frontotemporal dementia 2021-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 406 of the MAPT protein (p.Arg406Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs63750424, ExAC 0.002%). 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. ClinVar contains an entry for this variant (Variation ID: 14247). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MAPT function (PMID: 10797541, 11102510, 11756436, 19304664, 21339331, 24150109). For these reasons, this variant has been classified as Pathogenic.
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
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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