19-52212718-C-T

Variant names:

• chr19-52212718-C-T
• rs786205228
• NM_014225.6:c.536C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_014225.6(PPP2R1A):​c.536C>T​(p.Pro179Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.92
• Publications: 62 publications found

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

PPP2R1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Houge-Janssens syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_014225.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-52212718-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1699184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 19-52212718-C-T is Pathogenic according to our data. Variant chr19-52212718-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 190313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.536C>T	p.Pro179Leu	missense_variant	Exon 5 of 15	ENST00000322088.11	NP_055040.2
PPP2R1A	NR_033500.2	n.480C>T		non_coding_transcript_exon_variant	Exon 4 of 14
PPP2R1A	NM_001363656.2	c.-2C>T		5_prime_UTR_variant	Exon 5 of 15		NP_001350585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.536C>T	p.Pro179Leu	missense_variant	Exon 5 of 15	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000435 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jan 23, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:1

Nov 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Houge-Janssens syndrome 2 Pathogenic:1

Mar 12, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PPP2R1A-related neurodevelopmental disorders Pathogenic:1

Mar 26, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

PPP2R1A-related disorder Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		6.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.4	D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.024	D;.
Sift4G	Uncertain	0.047	D;D
Polyphen		0.94	P;.
Vest4		0.75
MutPred		0.80		Loss of phosphorylation at T178 (P = 0.0578);.;
MVP		0.75
MPC		2.6
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.85
gMVP		0.90
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205228; hg19: chr19-52715971; COSMIC: COSV59042841; COSMIC: COSV59042841;