Submissions for variant NM_001377265.1(MAPT):c.1630G>A (p.Ala544Thr)

gnomAD frequency: 0.00179  dbSNP: rs143624519

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000356485	SCV000403480	likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532567	SCV000632354	uncertain significance	Frontotemporal dementia	2025-01-29	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 152 of the MAPT protein (p.Ala152Thr). This variant is present in population databases (rs143624519, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Parkinson disease, frontotemporal dementia (FTD), or Alzheimer disease (AD), however this variant has also been reported in control populations. A single study found that this variant increases the risk for both FTD (OR =3.0, CI: 1.6–5.6, P= 0.0005) and AD (OR=2.3, CI: 1.3–4.2, P=0.004), but this result has not been independently replicated (PMID: 21176711, 22312439, 22556362, 22595371, 22906081, 23518664, 26333800, 33612544). It has also been observed to segregate with disease in related individuals. This variant is also known as NM_016835.4:c.1405G>A p.(Ala469Thr). ClinVar contains an entry for this variant (Variation ID: 323645). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAPT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 22556362, 26931567, 28334843). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001531268	SCV001746292	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MAPT: BP4, BS2
GeneDx	RCV001531268	SCV001873507	benign	not provided	2019-03-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26916334, 29525180, 27594585, 28594853, 28334843, 23518664, 24319659, 26931569, 27776828, 26333800, 21176711, 23692670, 22312439, 23990795, 22595371, 22556362, 22906081, 30279455)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526663	SCV005039112	likely benign	not specified	2024-03-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001531268	SCV005367822	likely risk allele	not provided	2024-03-29	criteria provided, single submitter	clinical testing	This variant has been reported to cause an increased risk of developing clinical features associated with this gene. This variant is statistically more frequent in individuals affected with frontotemporal dementia (FTD) and Alzheimer disease (AD) than in the general population and/or healthy controls (PMID: 22556362), even though its frequency in the general population is higher than would generally be expected for pathogenic variants in this gene (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) It has been reported in multiple studies that Ala152Thr is associated with a wide range of diagnoses, including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinsonism, progressive supranuclear palsy (PSP), and others. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 26916334, 26931567, 26931569, 30590647, 28334843)