chr19-52212718-C-T

Position:

• chr19-52212718-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a region_of_interest SV40 small T antigen binding (size 154) in uniprot entity 2AAA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014225.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R1A. . Gene score misZ 4.4565 (greater than the threshold 3.09). Trascript score misZ 5.4176 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
• 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 id is 190313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-52212718-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.536C>T	p.Pro179Leu	missense_variant	5/15	1	NM_014225.6	ENSP00000324804	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2020

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. -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 12, 2015

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

PPP2R1A-related neurodevelopmental disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 26, 2020

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

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;.
MutationTaster	Benign	1.0	D;D;D
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

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

Publications

LitVar

Other links and lift over

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