rs786205228

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-52212718-C-A
• chr19-52212718-C-G
• chr19-52212718-C-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>A​(p.Pro179His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.92
• Publications: 1 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-T is described in ClinVar as Pathogenic. ClinVar VariationId is 190313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 19-52212718-C-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.536C>A	p.Pro179His	missense_variant	Exon 5 of 15	ENST00000322088.11	NP_055040.2
PPP2R1A	NR_033500.2	n.480C>A		non_coding_transcript_exon_variant	Exon 4 of 14
PPP2R1A	NM_001363656.2	c.-2C>A		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>A	p.Pro179His	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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Houge-Janssens syndrome 2 Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		6.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.5	D;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.76		Gain of catalytic residue at P179 (P = 0.0343);.;
MVP		0.66
MPC		2.8
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.85
Mutation Taster		=16/84	disease causing

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: COSV105226226;