ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.1309A>G (p.Ile437Val)

gnomAD frequency: 0.00002  dbSNP: rs764971634
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV001289154 SCV001476789 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001871727 SCV002223936 pathogenic Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 2024-11-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the PSEN1 protein (p.Ile437Val). This variant is present in population databases (rs764971634, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of PSEN1-related conditions (PMID: 26242991, 31996268; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PSEN1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 18,931 individuals referred to our laboratory for PSEN1 testing. ClinVar contains an entry for this variant (Variation ID: 995216). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 19005074, 27930341). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001289154 SCV004031490 uncertain significance not provided 2023-02-28 criteria provided, single submitter clinical testing Previously reported in individuals with phenotypes consistent with PSEN1-related dementia (Nicolas G et al.,2016; Orme et al., 2020); Published functional studies suggest that the variant causes reduced production and activity of A42 and A40 (Sun et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32985163, 31996268, 19005074, 30801016, 26242991, 30412504, 27930341)

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