VCV000441275.14 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 441275 Accession: VCV000441275.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q24 4: 101083202 (GRCh38) [ NCBI UCSC ] 4: 102004359 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 25, 2018	Aug 25, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000944.5:c.844G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000935.1:p.Glu282Lys	missense
NM_001130691.2:c.844G>A	NP_001124163.1:p.Glu282Lys	missense
NM_001130692.2:c.844G>A	NP_001124164.1:p.Glu282Lys	missense
NC_000004.12:g.101083202C>T
NC_000004.11:g.102004359C>T

... more HGVS ... less HGVS

Protein change

E282K

Other names

Canonical SPDI

NC_000004.12:101083201:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA357948412 OMIM: 114105.0005 dbSNP: rs1553923787 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PPP3CA		-	-	GRCh38 GRCh37	435	464

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Epileptic encephalopathy, infantile or early childhood, 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 25, 2022	RCV000509989.8
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Nov 14, 2016	RCV000624048.2
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 3, 2023	RCV002269282.5
Epileptic encephalopathy	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2024	RCV003483646.2
Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development Epileptic encephalopathy, infantile or early childhood, 1	Pathogenic (1)	criteria provided, single submitter	-	RCV003883152.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy, infantile or early childhood, 1 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001571660.1 First in ClinVar: Apr 24, 2021 Last updated: Apr 24, 2021	Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Autism (present) , Electrical status epilepticus in sleep but no definite clinical seizure (present) Testing laboratory: GeneDx
Likely pathogenic (Nov 14, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741838.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (3) PubMed: 8524402‚ 8052858‚ 28942967 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Seizures (present) , Cleft palate (present) , Clubfoot (present) , Absence seizures (present) , Generalized tonic-clonic seizures (present) , Myoclonic … (more) Global developmental delay (present) , Seizures (present) , Cleft palate (present) , Clubfoot (present) , Absence seizures (present) , Generalized tonic-clonic seizures (present) , Myoclonic spasms (present) , EEG with spike-wave complexes (present) , Epileptiform EEG discharges (present) (less) Sex: female Ethnicity/Population group: South Asian
Pathogenic (Aug 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy, infantile or early childhood, 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581862.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PS4, PM2_SUP, PP2	Number of individuals with the variant: 1 Sex: female
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy, infantile or early childhood, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767479.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 28942967‚ 29432562‚ 32593294‚ 33963760 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 91 (MIM#617711), and arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development (MIM#618265), respectively (PMIDs: 32593294, 29432562). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (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 high conservation. (I) 0600 - Variant is located in the annotated protein phosphatase 2B (PP2B) catalytic domain (PMID: 28942967). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in multiple affected individuals (PMIDs: 28942967, 33963760). (SP) 1010 - Functional evidence for this variant is inconclusive. Overexpression studies using yeast showed the mutant maintained tolerance to growth condition with high extracellular Ca2+, similar to wild-type (PMID: 29432562). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002552746.2 First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023	Comment: 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; … (more) 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) (less)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epileptic encephalopathy Affected status: yes Allele origin: germline	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV004232388.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 25741868 Sex: male
Pathogenic (Sep 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293207.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28942967 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development Epileptic encephalopathy, infantile or early childhood, 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: de novo	Molecular Genetics Lab, CHRU Brest Accession: SCV004697645.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196791.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Mar 15, 2021)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 91 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000607751.3 First in ClinVar: Oct 23, 2017 Last updated: Mar 18, 2021	Publications: PubMed (1) PubMed: 28942967 Comment on evidence: In 2 unrelated patients (individuals 5 and 6) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.844G-A … (more) In 2 unrelated patients (individuals 5 and 6) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.844G-A transition (c.844G-A, NM_000944.4) in the PPP3CA gene, resulting in a glu282-to-lys (E282K) substitution in the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patients cells were not performed. One patient was of Pakistani origin and the other was of mixed European and Ashkenazi descent. (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 91 (MIM#617711), and arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development (MIM#618265), respectively (PMIDs: 32593294, 29432562). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (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 high conservation. (I) 0600 - Variant is located in the annotated protein phosphatase 2B (PP2B) catalytic domain (PMID: 28942967). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in multiple affected individuals (PMIDs: 28942967, 33963760). (SP) 1010 - Functional evidence for this variant is inconclusive. Overexpression studies using yeast showed the mutant maintained tolerance to growth condition with high extracellular Ca2+, similar to wild-type (PMID: 29432562). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy.	Panneerselvam S	Clinical genetics	2021	PMID: 33963760
Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report.	Yang S	BMC pediatrics	2020	PMID: 32593294
Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders.	Mizuguchi T	Human molecular genetics	2018	PMID: 29432562
De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.	Myers CT	American journal of human genetics	2017	PMID: 28942967
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.	Kissinger CR	Nature	1995	PMID: 8524402
Calcineurin inhibition of dynamin I GTPase activity coupled to nerve terminal depolarization.	Liu JP	Science (New York, N.Y.)	1994	PMID: 8052858

Text-mined citations for rs1553923787 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1553923787 ...