ClinVar Miner

Submissions for variant NM_014225.6(PPP2R1A):c.656C>T (p.Ser219Leu)

dbSNP: rs1555791268
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623695 SCV000742123 uncertain significance Inborn genetic diseases 2017-01-18 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000824836 SCV000965730 likely pathogenic Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome 2016-01-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000824836 SCV001440102 likely pathogenic Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome 2021-03-01 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
CeGaT Center for Human Genetics Tuebingen RCV001531910 SCV001747240 likely pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000824836 SCV001870374 uncertain significance Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome 2021-07-16 criteria provided, single submitter research ACMG codes:PM2, PP2, PP3
GeneDx RCV001531910 SCV002028206 pathogenic not provided 2021-11-15 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29100083, 26920370, 31531803)
3billion RCV000824836 SCV002058466 likely pathogenic Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome 2022-01-03 criteria provided, single submitter clinical testing he variant has been previously reported as de novo in a similarly affected individual (PMID:29100083, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPP2R1A related disorder (PMID:29100083, PS1_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae RCV001531910 SCV002246436 pathogenic not provided 2021-11-25 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 219 of the PPP2R1A protein (p.Ser219Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R1A-related conditions (PMID: 29100083, 31531803, 33106617; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services,Illumina RCV000824836 SCV002540240 pathogenic Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome 2021-12-10 criteria provided, single submitter clinical testing The PPP2R1A c.656C>T (p.Ser219Leu) missense variant results in the substitution of serine at amino acid position 219 with leucine. This variant has been reported in a de novo heterozygous state in five individuals with PPP2R1A-related neurodevelopmental disorder (Hamdan et al. 2017; Zhang et al. 2020; Lenaerts et al. 2021). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies in HEK293 cells by Lenaerts et al. (2021) demonstrated that the c.656C>T variant showed near complete loss of binding of the B55α and B56β regulatory subunits, while binding to PP2A-C subunit was reduced by about 50%. Based on the available evidence, the c.656C>T (p.Ser219Leu) variant is classified as pathogenic for PPP2R1A-related neurodevelopmental disorder.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000824836 SCV001499946 pathogenic Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome no assertion criteria provided clinical testing

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