ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.1630G>A (p.Ala544Thr) (rs143624519)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000356485 SCV000403480 likely benign MAPT-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000532567 SCV000632354 uncertain significance Frontotemporal dementia 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 152 of the MAPT protein (p.Ala152Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs143624519, ExAC 0.2%). This variant has been reported to segregate with Parkinson s disease (PD) with dementia in a single family (PMID: 22595371) and has been reported in many individuals with frontotemporal dementia (FTD) and Alzheimer's disease (AD) (PMID: 21176711, 22312439, 22556362, 26333800, 22906081, 22595371, 23518664). However, this variant has also been reported at relatively high frequency in control populations (PMID: 26333800, 22556362, 22312439). A single study found that this variant increases the risk for both FTD (OR =3.0, CI: 1.6 5.6, P= 0.0005) and AD (OR=2.3, CI: 1.3 4.2, P=0.004) (PMID: 22556362), but this result has not been independently replicated. ClinVar contains an entry for this variant (Variation ID: 323645). In vitro studies have shown that this missense change increases the formation of MAPT protein oligomers (PMID: 22556362). Zebrafish models have shown disruption of proteasome function and delayed tau clearance in vivo (PMID:28334843). Transgenic mouse models have shown age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity (PMID: 26931567). In summary, this variant has been reported in affected individuals but is also present at a relatively high frequency in control populations. The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531268 SCV001746292 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
GeneDx RCV001531268 SCV001873507 benign not provided 2019-03-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26916334, 29525180, 27594585, 28594853, 28334843, 23518664, 24319659, 26931569, 27776828, 26333800, 21176711, 23692670, 22312439, 23990795, 22595371, 22556362, 22906081, 30279455)

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