NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 12, 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:: RCV000412854.12

Allele description [Variation Report for NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp)]

NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp)

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.544C>T (p.Arg182Trp)

HGVS:

NC_000019.10:g.52212726C>T
NG_047068.1:g.27925C>T
NM_001363656.2:c.7C>T
NM_014225.6:c.544C>TMANE SELECT
NP_001350585.1:p.Arg3Trp
NP_055040.2:p.Arg182Trp
NC_000019.9:g.52715979C>T
NM_014225.5:c.544C>T
NR_033500.2:n.488C>T
P30153:p.Arg182Trp

Protein change:

R182W; ARG182TRP

Links:

UniProtKB: P30153#VAR_074489; OMIM: 605983.0001; dbSNP: rs786205227

NCBI 1000 Genomes Browser:

rs786205227

Molecular consequence:

NM_001363656.2:c.7C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014225.6:c.544C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_033500.2:n.488C>T - 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
SCV000491305	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 29, 2021)	germline	clinical testing	Citation Link,
SCV001585609	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25533962, 26168268, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000491305

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 29, 2021)

germline

clinical testing

Citation Link,

SCV001585609

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 12, 2023)

germline

clinical testing

PubMed (3)
[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

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study..

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.

PubMed [citation]

PMID:: 25533962
PMCID:: PMC5955210

Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M, Vogt J, McKee S, Tolmie JL, Cordeiro N, Kleefstra T, Willemsen MH, Reijnders MR, Berland S, Hayman E, Lahat E, Brilstra EH, van Gassen KL, Zonneveld-Huijssoon E, de Bie CI, Hoischen A, Eichler EE, et al.

J Clin Invest. 2015 Aug 3;125(8):3051-62. doi: 10.1172/JCI79860. Epub 2015 Jul 13.

PubMed [citation]

PMID:: 26168268
PMCID:: PMC4623570

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000491305.4

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

Description

Published functional studies demonstrate that R182W affects PP2A holoenzyme formation, and PR72 binding is prevented due to the presence of the R182W mutant protein. Additionally, PP2A phosphatase activity is decreased for the R182W mutant compared to the wild type (Houge et al., 2015).; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25533962, 26168268, 28628100, 28867141, 28135719, 32565546)

#	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, SCV001585609.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the PPP2R1A protein (p.Arg182Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and developmental delay (PMID: 25533962, 26168268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190312). 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%. Experimental studies have shown that this missense change affects PPP2R1A function (PMID: 26168268). For these reasons, this variant has been classified as Pathogenic.

#	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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