ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.280G>A (p.Val94Met)

gnomAD frequency: 0.00001  dbSNP: rs63750831
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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 RCV001854471 SCV002216952 uncertain significance Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 2022-06-27 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects PSEN1 function (PMID: 27930341). 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. 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 PSEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 98008). This missense change has been observed in individual(s) with early-onset Alzheimer disease (PMID: 11568920). This variant is present in population databases (rs63750831, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the PSEN1 protein (p.Val94Met).
VIB Department of Molecular Genetics, University of Antwerp RCV000084287 SCV000116423 not provided not provided no assertion provided not provided
PreventionGenetics, part of Exact Sciences RCV004752745 SCV005365450 uncertain significance PSEN1-related disorder 2024-06-27 no assertion criteria provided clinical testing The PSEN1 c.280G>A variant is predicted to result in the amino acid substitution p.Val94Met. This variant has been reported in an individual with early-onset Alzheimer disease (Arango et al. 2001. PubMed ID: 11568920). An in vitro functional study demonstrated that expression of this variant negatively affected the combined production of Aβ42 and Aβ40 compared to wildtype (Figure 3, Sun et al. 2016. PubMed ID: 27930341). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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