Submissions for variant NM_014225.6(PPP2R1A):c.536C>T (p.Pro179Leu)

dbSNP: rs786205228

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000391040	SCV000329952	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: cellular binding assays show impaired PP2A holoenzyme formation and decreased PP2A activity compared to wild-type (Houge et al., 2015); Not observed at significant frequency 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: 28867141, 27879972, 25533962, 26168268, 28135719, 33106617, 31785789)
Illumina Laboratory Services, Illumina	RCV001249733	SCV001423764	pathogenic	PPP2R1A-related neurodevelopmental disorders	2020-03-26	criteria provided, single submitter	clinical testing	The PPP2R1A c.536C>T (p.Pro179Leu) variant is a missense variant that has been reported in a heterozygous de novo state in two individuals with a neurodevelopmental disorder (Fitzgerald et al. 2015; Houge et al. 2015). One of the affected individuals was noted to have hypotonia, speech impairment, severe intellectual disability, corpus callosum agenesis, cortical visual impairment and microcephaly and was unable to walk unsupported (Houge et al. 2015). The other individual presented with intellectual disability, joint hypermobility, aplasia/hypoplasia of the corpus callosum, deviation of the 5th finger, pectus excavatum, and seizures. The variant was absent from 1013 controls (Fitzgerald et al. 2015) and is absent from the Genome Aggregation Database in a region of good sequence coverage and is therefore presumed to be rare. The Pro179 residue is located in the fifth HEAT domain, and HEAT domains are thought to aid in interaction with the regulatory and catalytic subunits of the PP2A holoenzyme (Houge et al. 2015). Expression of Pro179Leu variant protein in HEK293 cells showed 50% reduced binding to the catayltic subunit as well as 50% reduction in phosphatase activity (Houge et al. 2015). Based on the collective evidence and application of ACMG criteria, the p.Pro179Leu variant is classified as pathogenic for PPP2R1A-related neurodevelopmental disorder.
Ambry Genetics	RCV001266291	SCV001444464	pathogenic	Inborn genetic diseases	2020-01-23	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.536C>T (p.P179L) alteration is located in coding exon 5 of the PPP2R1A gene. This alteration results from a C to T substitution at nucleotide position 536, causing the proline (P) at amino acid position 179 to be replaced by a leucine (L). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the PPP2R1A c.536C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ The PPP2R1A c.536C>T (p.P179L) alteration has been reported previously as a de novo alteration in two unrelated individuals with similar neurodevelopmental phenotypes (Hough, 2015; The Deciphering Developmental Disorders Study, 2015). The patient reported by Hough (2015) was a 3.5 year old girl with hypotonia, intellectual disability, delayed language, cortical visual impariment, microcephaly, and agenesis of the corpus callosum. This alteration has been identified as a de novo event in multiple additional individuals (Ambry internal data). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P179 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis using cellular binding assays demonstrated that the P179L alteration affected Ser/Thr protein phosphatase 2A (PP2A) holoenzyme formation (Hough, 2015). Measurement of PP2A activity showed decreased phosphatase activity of P179L compared to wild-type protein indicating this alteration impairs catalytic activity. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.P179L alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000170501	SCV000222933	pathogenic	Houge-Janssens syndrome 2	2015-03-12	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004725019	SCV005338058	pathogenic	PPP2R1A-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The PPP2R1A c.536C>T variant is predicted to result in the amino acid substitution p.Pro179Leu. This variant has been reported as a de novo finding in multiple individuals with developmental disorders (see, for example, Table S4, Fitzgerald et al. 2015. PubMed ID: 25533962; Houge et al. 2015. PubMed ID: 26168268; Lenaerts et al. 2020. PubMed ID: 33106617). This variant has not been reported in a large population database, indicating it is rare. In vitro experimental studies suggest this variant impacts protein function (Houge et al. 2015. PubMed ID: 26168268; Lenaerts et al. 2020. PubMed ID: 33106617). Another missense variant affecting this amino acid (p.Pro179His) has also been reported in an individual with PPP2R1A-related developmental disorder (Baker et al. 2022. PubMed ID: 36209351). This variant is interpreted as pathogenic.