ClinVar Miner

Submissions for variant NM_001377265.1(MAPT):c.220+2503C>T

gnomAD frequency: 0.00002  dbSNP: rs138293088
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000803671 SCV000943553 uncertain significance Frontotemporal dementia 2021-06-16 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine 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. This variant has been observed in an individual affected with amyotrophic lateral sclerosis (PMID: 23881933). This variant is present in population databases (rs138293088, ExAC 0.02%). This sequence change replaces threonine with methionine at codon 95 of the MAPT protein (p.Thr95Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine.
Illumina Laboratory Services, Illumina RCV001123792 SCV001282659 benign MAPT-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526776 SCV005039123 uncertain significance not specified 2024-03-25 criteria provided, single submitter clinical testing Variant summary: MAPT c.284C>T (p.Thr95Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 238060 control chromosomes (gnomAD). c.284C>T has been reported in the literature in an individual affected with ALS as well as unaffected controls. This report does not provide unequivocal conclusions about association of the variant with MAPT-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23881933). ClinVar contains an entry for this variant (Variation ID: 648859). Based on the evidence outlined above, the variant was classified as uncertain significance.

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