NM_014225.6:c.536C>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000329952: 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); SCV001423764: 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).; SCV001444464: 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.; SCV005338058: "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 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: 65 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: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329952: 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); SCV001423764: 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).; SCV001444464: 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.; SCV005338058: "In vitro experimental studies suggest this variant impacts protein function" (Houge et al. 2015. PubMed ID: 26168268; Lenaerts et al. 2020. PubMed ID: 33106617).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	NM_014225.6	MANE Select	c.536C>T	p.Pro179Leu	missense	Exon 5 of 15	NP_055040.2
	PPP2R1A	NM_001363656.2		c.-2C>T		5_prime_UTR	Exon 5 of 15	NP_001350585.1	B3KQV6
	PPP2R1A	NR_033500.2		n.480C>T		non_coding_transcript_exon	Exon 4 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.536C>T	p.Pro179Leu	missense	Exon 5 of 15	ENSP00000324804.6	P30153
	PPP2R1A	ENST00000454220.7	TSL:1	c.656C>T	p.Pro219Leu	missense	Exon 5 of 15	ENSP00000391905.3	C9J9C1
	PPP2R1A	ENST00000703398.1		c.578C>T	p.Pro193Leu	missense	Exon 5 of 15	ENSP00000515288.1	A0A994J3H1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000435 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Houge-Janssens syndrome 2 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	PPP2R1A-related disorder (1)
1	-	-	PPP2R1A-related neurodevelopmental disorders (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.91	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
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;