ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.1891G>A (p.Ala631Thr)

gnomAD frequency: 0.00067  dbSNP: rs63750096
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,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 2021-11-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 239 of the MAPT protein (p.Ala239Thr). This variant is present in population databases (rs63750096, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with frontotemporal dementia, Parkinson disease and Alzheimer's disease (PMID: 11912108, 22312439, 23053136, 25466404, 27094865). 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, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx RCV000084513 SCV001837260 benign not provided 2019-01-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17071927, 25466404, 23053136)
VIB Department of Molecular Genetics, University of Antwerp RCV000084513 SCV000116649 not provided not provided no assertion provided not provided
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000084513 SCV001551959 uncertain significance not provided no assertion criteria provided clinical testing The MAPT p.Ala239Thr variant was identified in 5/91 individuals with late-onset Parkinson's Disease (age of onset 62-87) and in 1/96 control individuals (Petersen_2015_PMID:25466404). The variant was also identified in a woman with frontotemporal lobar degeneration but was not found in her two brothers with amyotrophic lateral sclerosis; the woman and her brothers also all carried an intronic GGGGCC hexanucleotide repeat expansion in C9ORF72 (King_2013_PMID:23053136). A British patient with frontotemporal dementia with a tau‚Äênegative, microvacuolar‚Äêtype histology was also reported to carry the MAPT p.A239T variant (Pickering-Brown_2002_PMID:11912108). The p.A239T variant was also identified in 4/439 late-onset Alzheimer disease (AD) families, 4/1,806 sporadic AD cases and 4/1,346 elderly controls (Cruchaga_2012_PMID:22312439). The variant was identified in dbSNP (ID: rs63750096), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae and as likely benign by Illumina). The variant was not identified in databases. The variant was identified in control databases in 177 of 279944 chromosomes at a frequency of 0.0006323 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 153 of 127156 chromosomes (freq: 0.001203), African in 14 of 24686 chromosomes (freq: 0.000567), European (Finnish) in 4 of 24990 chromosomes (freq: 0.00016), Latino in 5 of 35350 chromosomes (freq: 0.000141) and Other in 1 of 7152 chromosomes (freq: 0.00014), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Ala239 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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