ClinVar Miner

Submissions for variant NM_003900.5(SQSTM1):c.374A>G (p.Asn125Ser)

gnomAD frequency: 0.00006  dbSNP: rs769325755
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001041398 SCV001205011 uncertain significance Frontotemporal dementia and/or amyotrophic lateral sclerosis 1; Paget disease of bone 2, early-onset 2025-01-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 125 of the SQSTM1 protein (p.Asn125Ser). This variant is present in population databases (rs769325755, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SQSTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 839604). 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 SQSTM1 protein function with a negative predictive value of 80%. 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.
GeneDx RCV001546334 SCV001765831 uncertain significance not provided 2023-06-20 criteria provided, single submitter clinical testing In a study of individuals from a large FTLD cohort, N125S was only identified in control alleles (van der Zee et al., 2014); Reported previously in an individual with dementia; however, the variant was also observed in controls (Cuyvers et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24899140, 25796131)
PreventionGenetics, part of Exact Sciences RCV004536076 SCV004118540 uncertain significance SQSTM1-related disorder 2022-11-29 criteria provided, single submitter clinical testing The SQSTM1 c.374A>G variant is predicted to result in the amino acid substitution p.Asn125Ser. This variant was reported in the control group of a frontotemporal lobar degeneration cohort study (van der Zee et al. 2014. PubMed ID: 24899140), however it was also reported in a cohort of individuals with a personal or family history of Alzheimer disease (Cuyvers et al. 2015. PubMed ID: 25796131). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-179250930-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.