Submissions for variant NM_006245.4(PPP2R5D):c.751G>C (p.Asp251His)

dbSNP: rs1762178916

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001265485	SCV002523214	likely pathogenic	Hogue-Janssens syndrome 1	2024-10-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 supporting, PM1, PM5, PM6, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537678	SCV003340565	pathogenic	not provided	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 251 of the PPP2R5D protein (p.Asp251His). 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; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 984892). 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, 32371413; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV001265485	SCV005046474	pathogenic	Hogue-Janssens syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing
GeneDx	RCV002537678	SCV005442991	pathogenic	not provided	2024-07-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a severe impacts on the ability of PPP2R5D to bind other enzyme subunits and a moderate impairment on substrate binding (PMID: 36216457); 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)
GenomeConnect - Simons Searchlight	RCV001265485	SCV001443629	likely pathogenic	Hogue-Janssens syndrome 1	2018-02-27	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-02-27 and interpreted as Likely Pathogenic. Variant was initially reported on 2015-09-10 by GTR ID of laboratory name Unite de Recherche Inserm Institut IMAGINE. The reporting laboratory might also submit to ClinVar.