ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.2179G>A (p.Gly727Ser)

dbSNP: rs63750095
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003514309 SCV004298244 likely pathogenic Frontotemporal dementia 2023-02-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 335 of the MAPT protein (p.Gly335Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early-onset frontotemporal dementia (PMID: 17186252, 23047372; Invitae). ClinVar contains an entry for this variant (Variation ID: 98228). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAPT protein function. Experimental studies have shown that this missense change affects MAPT function (PMID: 17186252). This variant disrupts the p.Gly335Val amino acid residue in MAPT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15765246). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp RCV000084545 SCV000116681 not provided not provided no assertion provided not provided

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