VCV000039975.6 - ClinVar

NM_001367534.1(CAMK2G):c.875G>C (p.Arg292Pro)

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.

(4)

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_001367534.1(CAMK2G):c.875G>C (p.Arg292Pro)

Variation ID: 39975 Accession: VCV000039975.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.2 10: 73842486 (GRCh38) [ NCBI UCSC ] 10: 75602244 (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	Apr 4, 2013	Oct 26, 2024	Oct 2, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_001367534.1:c.875G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001354463.1:p.Arg292Pro	missense
NM_001204492.2:c.875G>C	NP_001191421.1:p.Arg292Pro	missense
NM_001222.4:c.875G>C	NP_001213.2:p.Arg292Pro	missense
NM_001320898.2:c.875G>C	NP_001307827.1:p.Arg292Pro	missense
NM_001367514.1:c.851G>C	NP_001354443.1:p.Arg284Pro	missense
NM_001367516.1:c.875G>C	NP_001354445.1:p.Arg292Pro	missense
NM_001367517.1:c.875G>C	NP_001354446.1:p.Arg292Pro	missense
NM_001367518.1:c.875G>C	NP_001354447.1:p.Arg292Pro	missense
NM_001367519.1:c.875G>C	NP_001354448.1:p.Arg292Pro	missense
NM_001367520.1:c.875G>C	NP_001354449.1:p.Arg292Pro	missense
NM_001367521.1:c.875G>C	NP_001354450.1:p.Arg292Pro	missense
NM_001367522.1:c.875G>C	NP_001354451.1:p.Arg292Pro	missense
NM_001367523.1:c.875G>C	NP_001354452.1:p.Arg292Pro	missense
NM_001367524.1:c.629G>C	NP_001354453.1:p.Arg210Pro	missense
NM_001367525.1:c.851G>C	NP_001354454.1:p.Arg284Pro	missense
NM_001367526.1:c.875G>C	NP_001354455.1:p.Arg292Pro	missense
NM_001367527.1:c.875G>C	NP_001354456.1:p.Arg292Pro	missense
NM_001367528.1:c.875G>C	NP_001354457.1:p.Arg292Pro	missense
NM_001367529.1:c.875G>C	NP_001354458.1:p.Arg292Pro	missense
NM_001367530.1:c.875G>C	NP_001354459.1:p.Arg292Pro	missense
NM_001367531.1:c.875G>C	NP_001354460.1:p.Arg292Pro	missense
NM_001367532.1:c.851G>C	NP_001354461.1:p.Arg284Pro	missense
NM_001367533.1:c.875G>C	NP_001354462.1:p.Arg292Pro	missense
NM_001367535.1:c.875G>C	NP_001354464.1:p.Arg292Pro	missense
NM_001367536.1:c.875G>C	NP_001354465.1:p.Arg292Pro	missense
NM_001367537.1:c.563G>C	NP_001354466.1:p.Arg188Pro	missense
NM_001367538.1:c.563G>C	NP_001354467.1:p.Arg188Pro	missense
NM_001367539.1:c.629G>C	NP_001354468.1:p.Arg210Pro	missense
NM_001367540.1:c.209G>C	NP_001354469.1:p.Arg70Pro	missense
NM_001367541.1:c.875G>C	NP_001354470.1:p.Arg292Pro	missense
NM_001367542.1:c.122G>C	NP_001354471.1:p.Arg41Pro	missense
NM_001367543.1:c.875G>C	NP_001354472.1:p.Arg292Pro	missense
NM_001367544.1:c.875G>C	NP_001354473.1:p.Arg292Pro	missense
NM_001367545.1:c.875G>C	NP_001354474.1:p.Arg292Pro	missense
NM_001367546.1:c.875G>C	NP_001354475.1:p.Arg292Pro	missense
NM_001367547.1:c.875G>C	NP_001354476.1:p.Arg292Pro	missense
NM_001367548.1:c.875G>C	NP_001354477.1:p.Arg292Pro	missense
NM_172169.3:c.875G>C	NP_751909.1:p.Arg292Pro	missense
NM_172170.5:c.875G>C	NP_751910.1:p.Arg292Pro	missense
NM_172171.3:c.875G>C	NP_751911.1:p.Arg292Pro	missense
NM_172173.3:c.875G>C	NP_751913.1:p.Arg292Pro	missense
NR_160040.1:n.969G>C		non-coding transcript variant
NR_160041.1:n.945G>C		non-coding transcript variant
NR_160042.1:n.914G>C		non-coding transcript variant
NR_160044.1:n.965G>C		non-coding transcript variant
NR_160045.1:n.874G>C		non-coding transcript variant
NR_160046.1:n.1413G>C		non-coding transcript variant
NR_160047.1:n.1099G>C		non-coding transcript variant
NR_160263.1:n.982G>C		non-coding transcript variant
NC_000010.11:g.73842486C>G
NC_000010.10:g.75602244C>G
NG_029408.2:g.37106G>C

... more HGVS ... less HGVS

Protein change

R292P, R210P, R284P, R188P, R41P, R70P

Other names

Canonical SPDI

NC_000010.11:73842485:C:G

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: CA130678 OMIM: 602123.0001 dbSNP: rs397514627 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.
CAMK2G		-	-	GRCh38 GRCh37	73	91

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.
Intellectual disability, severe	Pathogenic (1)	no assertion criteria provided	Nov 15, 2012	RCV000033109.3
Autism Generalized hypotonia Global developmental delay Intellectual disability, severe	Likely pathogenic (1)	criteria provided, single submitter	Sep 21, 2016	RCV000678045.3
Intellectual developmental disorder 59	Pathogenic (2)	criteria provided, single submitter	Oct 2, 2020	RCV001588840.3

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.
Likely pathogenic (Sep 21, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, severe Autism Generalized hypotonia Global developmental delay (Sporadic) Affected status: yes Allele origin: de novo	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV000803661.1 First in ClinVar: Aug 31, 2018 Last updated: Aug 31, 2018	Comment: Parental studies indicated that this alteration is de novo in this individual. This alteration has been previously reported in the Human Gene Mutation Database and … (more) Parental studies indicated that this alteration is de novo in this individual. This alteration has been previously reported in the Human Gene Mutation Database and is associated with sporadic global developmental delay, hypotonia, and speech delay (GeneMatcher communication and de Ligt et al. (2012) N. Engl. J. Med. 367(20):1921-1929). This variant is not listed in the public SNP databases (ExAC, gnomAD) and is predicted to be deleterious or possibly damaging by multiple in silico algorithms (LRT, SIFT, PROVEAN, PolyPhen2-HumDiv). Based on the ACMG Guidelines for variant interpretation, using the criteria PS2, PS4 (downgraded to moderate), PM2, and PP3, this variant is classified as likely pathogenic. (less) Zygosity: Single Heterozygote
Pathogenic (Oct 02, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Intellectual developmental disorder 59 Affected status: yes Allele origin: de novo	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001815757.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (1) PubMed: 30184290 Comment: The de novo heterozygous p.Arg292Pro missense variant identified in the CAMK2G gene has been reported in at least two unrelated patients affected with a neurological … (more) The de novo heterozygous p.Arg292Pro missense variant identified in the CAMK2G gene has been reported in at least two unrelated patients affected with a neurological disorder [PMID: 23033978; PMID: 28191890; PMID: 30184290]. The variant has been reported as likely pathogenic in the ClinVar database [variation ID:39975]. The variant is absent from gnomAD(v3) database suggesting it is an extremely rare allele in the populations represented in this database. In vivoand in vitro functional analysis showed that the p.Arg292Pro variant exerts it’s pathogenic effect through gain-of-function mechanism via increased phosphotransferase activity, impaired neuronal maturation and impaired targeting of nuclear isoform [PMID: 30184290]. Based on the available evidence, the de novo p.Arg292Pro missense variant identified in the CAMK2G gene is reported here as Pathogenic. (less) Clinical Features: Immunodeficiency (present) , Intellectual disability (present) Zygosity: Single Heterozygote Secondary finding: no
Pathogenic (Nov 15, 2012)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 59 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056890.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 04, 2019	Publications: PubMed (2) PubMed: 23033978‚ 30184290 Comment on evidence: In a boy with autosomal dominant intellectual developmental disorder-59 (MRD59; 618522), de Ligt et al. (2012) identified a de novo heterozygous c.875G-C transversion (c.875G-C, NM_172171.2) … (more) In a boy with autosomal dominant intellectual developmental disorder-59 (MRD59; 618522), de Ligt et al. (2012) identified a de novo heterozygous c.875G-C transversion (c.875G-C, NM_172171.2) in the CAMK2G gene, resulting in an arg292-to-pro (R292P) substitution. The patient had normal array and MLL2 (602113) testing. Functional studies of the variant and studies of patient cells were not performed. Proietti Onori et al. (2018) identified a de novo heterozygous R292P mutation in a 5-year-old boy with MRD59 and noted that the substitution occurs in an autoregulatory domain that maintains the kinase in an inactive state in the absence of calcium/calmodulin. Transfection of the mutation into HEK293 cells resulted in lower protein expression compared to controls, suggesting that the mutant protein is unstable. Detailed functional expression studies showed that the mutation resulted in a dominant gain-of-function effect with increased phosphotransferase activity and constitutive activation, resulting in impaired neuronal migration in murine primary neurons. (less)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Intellectual developmental disorder 59 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091560.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

Parental studies indicated that this alteration is de novo in this individual. This alteration has been previously reported in the Human Gene Mutation Database and is associated with sporadic global developmental delay, hypotonia, and speech delay (GeneMatcher communication and de Ligt et al. (2012) N. Engl. J. Med. 367(20):1921-1929). This variant is not listed in the public SNP databases (ExAC, gnomAD) and is predicted to be deleterious or possibly damaging by multiple in silico algorithms (LRT, SIFT, PROVEAN, PolyPhen2-HumDiv). Based on the ACMG Guidelines for variant interpretation, using the criteria PS2, PS4 (downgraded to moderate), PM2, and PP3, this variant is classified as likely pathogenic.

Comment:

The de novo heterozygous p.Arg292Pro missense variant identified in the CAMK2G gene has been reported in at least two unrelated patients affected with a neurological disorder [PMID: 23033978; PMID: 28191890; PMID: 30184290]. The variant has been reported as likely pathogenic in the ClinVar database [variation ID:39975]. The variant is absent from gnomAD(v3) database suggesting it is an extremely rare allele in the populations represented in this database. In vivoand in vitro functional analysis showed that the p.Arg292Pro variant exerts it’s pathogenic effect through gain-of-function mechanism via increased phosphotransferase activity, impaired neuronal maturation and impaired targeting of nuclear isoform [PMID: 30184290]. Based on the available evidence, the de novo p.Arg292Pro missense variant identified in the CAMK2G gene is reported here as Pathogenic.

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
The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.	Proietti Onori M	Human mutation	2018	PMID: 30184290
Diagnostic exome sequencing in persons with severe intellectual disability.	de Ligt J	The New England journal of medicine	2012	PMID: 23033978

Text-mined citations for rs397514627 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001367534.1(CAMK2G):c.875G>C (p.Arg292Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514627 ...