ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.2091+16C>T

dbSNP: rs63751011
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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 RCV000084537 SCV000614050 pathogenic not provided 2017-04-04 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626752 SCV000747455 pathogenic Dementia 2017-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626753 SCV000747456 pathogenic Frontotemporal dementia; Memory impairment; Mental deterioration 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000687510 SCV000815082 pathogenic Frontotemporal dementia 2021-08-18 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the MAPT gene. It does not directly change the encoded amino acid sequence of the MAPT protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with frontotemporal dementia (PMID: 9641683, 11708988, 11912108, 11971081, 17923640, 19365643, 19766248, 19786698, 20045477, 28097206). It is commonly reported in individuals of Welsh ancestry (PMID: 19365643). This variant is also known as IVS10+16C>T or 10+16C>T. ClinVar contains an entry for this variant (Variation ID: 98222). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MAPT function (PMID: 9641683, 10329720, 19914360, 23680655, 26136155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000687510 SCV001150160 pathogenic Frontotemporal dementia 2018-01-23 criteria provided, single submitter clinical testing
GeneDx RCV000084537 SCV001767383 pathogenic not provided 2022-03-14 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant leads to aberrant splicing of exon 10 (Umeda et al., 2013; Hutton et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19365643, 27905268, 23885714, 10443890, 7783864, 8940276, 23680655, 19914360, 26136155, 27082848, 28097206, 29253099, 29930232, 11402146, 27594586, 25683866, 20045477, 19786698, 18525295, 14755449, 11708988, 11641718, 10446810, 10202939, 9392579, 9088499, 7936288, 11255441, 31031559, 31537715, 9641683, 19884572, 12847166, 15372253, 17923640, 19766248, 11971081, 11971082, 11912108, 31810826, 32804255, 31914217, 34099697, 10329720)
Molecular Genetics, Royal Melbourne Hospital RCV000687510 SCV002498672 pathogenic Frontotemporal dementia 2022-04-05 criteria provided, single submitter clinical testing This sequence change in MAPT is an intronic variant located in intron 10. This variant is absent from gnomAD v2.1 and v3.1. This variant is a common Welsh founder mutation and the most common variant in frontotemporal dementia (FTD) cases with British descent (PMID: 19365643). The variant has been reported to segregate with FTD in multiple families (PMID: 9641683). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may not impact splicing of MAPT. However, RT-PCR and mini-gene assays demonstrated that the variant increases exon 10 RNA expression expected to result in a change in the ratio of tau isoforms of three amino-acid repeats to those of four amino-acid repeats (PMID: 9641683). A transgenic mouse model of the variant also recapitulates the human phenotype and demonstrates much higher levels of four-repeat tau and the adult stage (PMID: 23680655). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PP1_Strong, PM2_Supporting, BP4.
OMIM RCV000687510 SCV000035578 pathogenic Frontotemporal dementia 2009-10-01 no assertion criteria provided literature only
VIB Department of Molecular Genetics, University of Antwerp RCV000084537 SCV000116673 not provided not provided no assertion provided not provided

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