ClinVar Miner

Submissions for variant NM_016835.4(MAPT):c.1666G>A (p.Ala556Thr) (rs63750096)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000325065 SCV000403485 benign MAPT-Related Spectrum Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000805364 SCV000945317 uncertain significance Frontotemporal dementia 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 239 of the MAPT protein (p.Ala239Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs63750096, ExAC 0.1%), and has an allele count higher than expected for a dominantly inherited pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with frontotemporal dementia (PMID: 23053136, 11912108), Parkinson disease (PMID: 25466404, 27094865), and Alzheimer's disease (PMID: 22312439). However, this variant has also been reported in unaffected individuals (PMID: 25466404, 22312439). ClinVar contains an entry for this variant (Variation ID: 98208). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, 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.
VIB Department of Molecular Genetics, University of Antwerp RCV000084513 SCV000116649 not provided not provided no assertion provided not provided

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