NM_014225.6(PPP2R1A):c.548G>A (p.Arg183Gln) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000520866.11

Allele description [Variation Report for NM_014225.6(PPP2R1A):c.548G>A (p.Arg183Gln)]

NM_014225.6(PPP2R1A):c.548G>A (p.Arg183Gln)

Gene:

PPP2R1A:protein phosphatase 2 scaffold subunit Aalpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.41

Genomic location:

Preferred name:

NM_014225.6(PPP2R1A):c.548G>A (p.Arg183Gln)

HGVS:

NC_000019.10:g.52212730G>A
NG_047068.1:g.27929G>A
NM_001363656.2:c.11G>A
NM_014225.6:c.548G>AMANE SELECT
NP_001350585.1:p.Arg4Gln
NP_055040.2:p.Arg183Gln
NC_000019.9:g.52715983G>A
NM_014225.5:c.548G>A
NR_033500.2:n.492G>A

Protein change:

R183Q

Links:

dbSNP: rs1057519947

NCBI 1000 Genomes Browser:

rs1057519947

Molecular consequence:

NM_001363656.2:c.11G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014225.6:c.548G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_033500.2:n.492G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622065	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 6, 2023)	germline	clinical testing	Citation Link,
SCV002129419	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 31, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31687265, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622065

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 6, 2023)

germline

clinical testing

Citation Link,

SCV002129419

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 31, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Newborn with Severe Ventriculomegaly: Expanding the PPP2R1A Gene Mutation Phenotype.

Wallace A, Caruso P, Karaa A.

J Pediatr Genet. 2019 Dec;8(4):240-243. doi: 10.1055/s-0039-1692414. Epub 2019 Jun 12.

PubMed [citation]

PMID:: 31687265
PMCID:: PMC6824891

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000622065.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed 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: 21381030, 23267135, 21435433, 26619011, 31687265, 35584285, 34958143)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002129419.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with clinical features of PPP2R1A-related intellectual disability (PMID: 31687265, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376506). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 183 of the PPP2R1A protein (p.Arg183Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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