ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.2064T>C (p.Asn688=)

dbSNP: rs63750912
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000015326 SCV001140677 pathogenic Frontotemporal dementia 2019-05-28 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000015326 SCV005086188 pathogenic Frontotemporal dementia 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with frontotemporal dementia, with or without parkinsonism (MIM#600274), Pick disease (MIM#172700), progressive supranuclear palsy (MIM#601104). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Interfamilial and intrafamilial phenotypic heterogeneity have been described (PMID: 23727082). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect. This synonymous variant has been shown to result in increased exon 10 inclusion (referring to the MANE transcript NM_001377265.1). This has been associated with increased expression of 4R tau isoforms, thereby disrupting the 3R:4R tau ratio which is crucial for proper functioning of tau (PMIDs: 11117553). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Multiple variants within this same intron and exon junction, such as +3, +15 and +16, have been shown to result in increased exon 10 inclusion similar to this synonymous variant (PMIDs: 11117553, 26136155, 26297556). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been regarded as likely pathogenic and pathogenic by clinical laboratories (LOVD, ClinVar) and has been detected in individuals with frontotemporal dementia (PMIDs: 11117553, 34305575) and progressive supranuclear palsy (PMID: 22818528). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000015326 SCV000035585 pathogenic Frontotemporal dementia 2000-12-01 no assertion criteria provided literature only
VIB Department of Molecular Genetics, University of Antwerp RCV000084525 SCV000116661 not provided not provided no assertion provided not provided

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