ClinVar Miner

Submissions for variant NM_006245.4(PPP2R5D):c.592G>A (p.Glu198Lys) (rs863225082)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000202079 SCV000256081 pathogenic not provided 2015-10-17 criteria provided, single submitter clinical testing p.Glu198Lys (GAA>AAA): c.592 G>A in exon 5 in the PPP2R5D Gene (NM_006245.3). The E198K pathogenic variant in the PPP2R5D gene has been reported previously as a de novo change in individuals with intellectual disability and variable additional features such as hypotonia (Fitzgerald et al., 2015; Houge et al., 2015). Functional studies found that cells expressing the E198K variant show deficient PP2A holoenzyme formation (Houge et al., 2015). The E198K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E198K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret E198K as a pathogenic variant. This variant has been observed de novo with confirmed parentage.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000170482 SCV000265598 pathogenic Mental retardation, autosomal dominant 35 2016-02-11 criteria provided, single submitter research
Institute of Human Genetics,Klinikum rechts der Isar RCV000170482 SCV000680348 pathogenic Mental retardation, autosomal dominant 35 2018-01-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623917 SCV000740978 likely pathogenic Inborn genetic diseases 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000170482 SCV000890084 pathogenic Mental retardation, autosomal dominant 35 2018-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000170482 SCV000920080 pathogenic Mental retardation, autosomal dominant 35 2018-10-30 criteria provided, single submitter clinical testing Variant summary: PPP2R5D c.592G>A (p.Glu198Lys) results in a conservative amino acid change (however with charge reversal) in a highly conserved acidic loop that faces and directly interacts with the catalytic subunit of PP2A; and a charge alteration in this acidic surface could potentially interrupt subunit interactions (Houge 2015). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246254 control chromosomes (gnomAD). The variant, c.592G>A, has been reported in the literature as a de novo mutation in multiple individuals affected with Mental retardation, autosomal dominant 35 (MRD35) (Houge 2015, Loveday 2015). These data indicate that the variant is very likely to be associated with disease. At least one of these publications also reported experimental evidence evaluating an impact on protein function, demonstrating loss of binding to the catalytic subunit, which leads to a defect in PP2A-B56delta-dependent dephosphorylation activity (Houge 2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (4x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000170482 SCV000965755 pathogenic Mental retardation, autosomal dominant 35 2015-01-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000170482 SCV000996151 pathogenic Mental retardation, autosomal dominant 35 2018-05-28 criteria provided, single submitter clinical testing This variant has been previously reported in the Human Gene Mutation Database (HGMD) and has been described as a recurrent de novo heterozygous change in patients with macrocephaly, developmental delay, hypotonia, and EEG abnormalities (PMID: 26168268, 28554332, 28628100, 25972378, 29296277). The c.592G>A (p.Glu198Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional analysis of cells expressing the p.Glu298Lys variant showed deficient PP2A holoenzyme formation (PMID: 26168268). This change is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.592G>A (p.Glu198Lys) variant is classified as Pathogenic.
OMIM RCV000170482 SCV000222909 pathogenic Mental retardation, autosomal dominant 35 2015-09-01 no assertion criteria provided literature only

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