Submissions for variant NM_006245.4(PPP2R5D):c.751G>T (p.Asp251Tyr)

dbSNP: rs1762178916

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001266286	SCV001444459	likely pathogenic	Inborn genetic diseases	2019-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001550149	SCV001770436	pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (PMID: 36216457); Not observed in large population cohorts (gnomAD); 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: 36216457)
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001779146	SCV002016291	pathogenic	Neurodevelopmental disorder	2021-08-31	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV002226760	SCV002505800	likely pathogenic	Hogue-Janssens syndrome 1	2021-08-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002226760	SCV002581185	likely pathogenic	Hogue-Janssens syndrome 1	2021-11-10	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002226760	SCV002769496	pathogenic	Hogue-Janssens syndrome 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. While loss of function was demonstrated, the possibility of dominant negative has not been excluded and is also a proposed mechanism (PMID: 32074998, 26168268). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Many alternative changes to alanine, valine and asparagine have been reported multiple times as likely pathogenic and pathogenic in ClinVar, including one de novo individual from VCGS. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, including one de novo individual (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002226760	SCV004045826	pathogenic	Hogue-Janssens syndrome 1	2023-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001550149	SCV004462180	uncertain significance	not provided	2024-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 251 of the PPP2R5D protein (p.Asp251Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP2R5D-related conditions (PMID: 36216457). ClinVar contains an entry for this variant (Variation ID: 985406). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 36216457). This variant disrupts the p.Asp251 amino acid residue in PPP2R5D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28867141, 31785789, 32371413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV002226760	SCV005046475	pathogenic	Hogue-Janssens syndrome 1	2023-09-05	criteria provided, single submitter	clinical testing