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 likely pathogenic Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 2023-08-31 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 19005074, 27930341). 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: 995216). This missense change has been observed in individuals with clinical features of PSEN1-related conditions (PMID: 26242991, 31996268; Invitae). This variant is present in population databases (rs764971634, gnomAD 0.005%). 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).
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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