ClinVar Miner

Submissions for variant NM_006245.4(PPP2R5D):c.758G>A (p.Arg253Gln)

gnomAD frequency: 0.00001  dbSNP: rs1131691266
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001696916 SCV000581731 pathogenic not provided 2024-07-02 criteria provided, single submitter clinical testing Reported heterozygous in a patient with autism and intellectual disability in published literature without additional clinical information or familial segregation information (PMID: 35813072, 37167322); 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: 35813072, 36833222, 37167322)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626280 SCV000746937 uncertain significance Hogue-Janssens syndrome 1 2020-05-03 criteria provided, single submitter clinical testing
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000626280 SCV000804328 uncertain significance Hogue-Janssens syndrome 1 2017-10-31 criteria provided, single submitter provider interpretation This 5 year old male has a history of global developmental delay, macrocephaly, hypotonia, vision abnormalities, torticollis, and plagiocephaly. This variant is absent from gnomAD but present in ExAC at a frequency of 0.0008121% overall. Computational models suggest that this variant is probably damaging to protein structure and/or function. The variant was inherited from the patient's father who has a history of dyslexia and who required learning supports in elementary school. Pathogenic de novo missense variants in PPP2R5D have been reported in individuals with intellectual disability, autism spectrum disorder, macrocephaly, hypotonia, increased height, seizures, and dysmorphic features (PMID:25972378; PMID:26576547).
Labcorp Genetics (formerly Invitae), Labcorp RCV001696916 SCV003328893 uncertain significance not provided 2022-03-12 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 429222). This variant has not been reported in the literature in individuals affected with PPP2R5D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the PPP2R5D protein (p.Arg253Gln).
Lifecell International Pvt. Ltd RCV000626280 SCV003924072 likely pathogenic Hogue-Janssens syndrome 1 criteria provided, single submitter clinical testing A Heterozygous Missense variant c.758G>A in Exon 7 of the PPP2R5D gene that results in the amino acid substitution p.Arg253Gln was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic and Uncertain Significance (variant ID: 429222). This variant has previously been reported for neurodevelopmental disorders (Krgovic D et al., 2022). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000626280 SCV004810253 uncertain significance Hogue-Janssens syndrome 1 2024-04-04 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000626280 SCV005416109 likely pathogenic Hogue-Janssens syndrome 1 criteria provided, single submitter clinical testing PM2_Supporting+PS4_Supporting+PM6_Supporting+PM5_Supporting+PP2+PM1

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