Submissions for variant NM_014225.6(PPP2R1A):c.536C>A (p.Pro179His)

dbSNP: rs786205228

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002273041	SCV002557599	likely pathogenic	Houge-Janssens syndrome 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with PPP2R1A-related neurodevelopmental disorder (MIM#616362) (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Pro179Leu) variant has been reported de novo in individuals with intellectual disability and neurodevelopmental delay (PMIDs: 26168268, 33106617; Decipher). This variant has also been classified as pathogenic by clinical diagnostic laboratories (ClinVar). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV005095976	SCV005757283	pathogenic	not provided	2024-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 179 of the PPP2R1A protein (p.Pro179His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features os PPP2R1A-related conditions (PMID: 36209351). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1699184). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPP2R1A protein function with a positive predictive value of 80%. This variant disrupts the p.Pro179 amino acid residue in PPP2R1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26168268, 33106617). 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.