ClinVar Miner

Submissions for variant NM_000447.3(PSEN2):c.184C>T (p.Arg62Cys)

gnomAD frequency: 0.00029  dbSNP: rs150400387
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000687794 SCV000815381 uncertain significance Alzheimer disease 4 2023-08-04 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. Experimental studies have shown that this missense change does not substantially affect PSEN2 function (PMID: 32087291). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 62 of the PSEN2 protein (p.Arg62Cys). This variant is present in population databases (rs150400387, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Alzheimer’s disease and/or frontotemporal dementia (PMID: 25104557, 25937274, 28008242, 28243073, 30279455, 34102969). ClinVar contains an entry for this variant (Variation ID: 567646). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated.
GeneDx RCV001584558 SCV001820246 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32087291, 28008242, 25104557, 30279455, 25937274, 28243073)
Fulgent Genetics, Fulgent Genetics RCV002485611 SCV002776618 uncertain significance Alzheimer disease 4; Dilated cardiomyopathy 1V 2022-02-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003420219 SCV004106173 uncertain significance PSEN2-related condition 2022-11-11 criteria provided, single submitter clinical testing The PSEN2 c.184C>T variant is predicted to result in the amino acid substitution p.Arg62Cys. This variant has been reported in individuals with early-onset Alzheimer disease, late-onset Alzheimer disease, and early-onset frontotemporal dementia (for example, see Sala Frigerio et al. 2015. PubMed ID: 25937274; Park et al. 2017. PubMed ID: 28243073; Table 3S in Koriath et al. 2018. PubMed ID: 30279455; An et al. 2016. PubMed ID: 28008242; Sassi et al. 2014. PubMed ID: 25104557). In experimental studies, the PSEN2 p.Arg62Cys substitution was reported not to affect in vitro Aβ42 or Aβ40 levels or the Aβ42/Aβ40 ratio (Hsu et al. 2020. PubMed ID: 32087291). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-227071448-C-T), which may be too common to be a disease-causing variant. 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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