NM_000944.5(PPP3CA):c.844G>A (p.Glu282Lys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 3, 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:: RCV002269282.4

Allele description [Variation Report for NM_000944.5(PPP3CA):c.844G>A (p.Glu282Lys)]

NM_000944.5(PPP3CA):c.844G>A (p.Glu282Lys)

Gene:

PPP3CA:protein phosphatase 3 catalytic subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q24

Genomic location:

Preferred name:

NM_000944.5(PPP3CA):c.844G>A (p.Glu282Lys)

HGVS:

NC_000004.12:g.101083202C>T
NM_000944.5:c.844G>AMANE SELECT
NM_001130691.2:c.844G>A
NM_001130692.2:c.844G>A
NP_000935.1:p.Glu282Lys
NP_001124163.1:p.Glu282Lys
NP_001124164.1:p.Glu282Lys
NC_000004.11:g.102004359C>T
NM_000944.4:c.844G>A

Protein change:

E282K; GLU282LYS

Links:

OMIM: 114105.0005; dbSNP: rs1553923787

NCBI 1000 Genomes Browser:

rs1553923787

Molecular consequence:

NM_000944.5:c.844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130691.2:c.844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130692.2:c.844G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase [Homo sapiens]
3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase [Homo sapiens]
gi|14714839|gb|AAH10570.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002552746	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 31, 2022)	germline	clinical testing	Citation Link,
SCV004293207	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28942967, 28492532
SCV005196791	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002552746

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 31, 2022)

germline

clinical testing

Citation Link,

SCV004293207

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 3, 2023)

germline

clinical testing

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

SCV005196791

Clinical Genetics Laboratory, Skane University Hospital Lund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 27, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.

Myers CT, Stong N, Mountier EI, Helbig KL, Freytag S, Sullivan JE, Ben Zeev B, Nissenkorn A, Tzadok M, Heimer G, Shinde DN, Rezazadeh A, Regan BM, Oliver KL, Ernst ME, Lippa NC, Mulhern MS, Ren Z, Poduri A, Andrade DM, Bird LM, Bahlo M, et al.

Am J Hum Genet. 2017 Oct 5;101(4):516-524. doi: 10.1016/j.ajhg.2017.08.013. Epub 2017 Sep 21.

PubMed [citation]

PMID:: 28942967
PMCID:: PMC5630160

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

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV002552746.2

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

Description

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: 11461966, 20700442, 10473536, 25262651, 27597899, 8052858, 15800199, 25245802, 3029762, 24140049, 22015374, 10627609, 28942967, 33963760)

#	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 Invitae, SCV004293207.1

#	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. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 282 of the PPP3CA protein (p.Glu282Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP3CA-related conditions (PMID: 28942967). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 441275). 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 PPP3CA protein function.

#	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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005196791.1

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

#	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

Last Updated: Aug 25, 2024

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