VCV000430922.40 - ClinVar

NM_001220.5(CAMK2B):c.416C>T (p.Pro139Leu)

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.

(14)

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_001220.5(CAMK2B):c.416C>T (p.Pro139Leu)

Variation ID: 430922 Accession: VCV000430922.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44243526 (GRCh38) [ NCBI UCSC ] 7: 44283125 (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	Dec 11, 2017	Jun 9, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001220.5:c.416C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001211.3:p.Pro139Leu	missense
NM_001293170.2:c.416C>T	NP_001280099.1:p.Pro139Leu	missense
NM_172078.3:c.416C>T	NP_742075.1:p.Pro139Leu	missense
NM_172079.3:c.416C>T	NP_742076.1:p.Pro139Leu	missense
NM_172080.3:c.416C>T	NP_742077.1:p.Pro139Leu	missense
NM_172081.3:c.416C>T	NP_742078.1:p.Pro139Leu	missense
NM_172082.3:c.416C>T	NP_742079.1:p.Pro139Leu	missense
NM_172083.3:c.416C>T	NP_742080.1:p.Pro139Leu	missense
NM_172084.3:c.416C>T	NP_742081.1:p.Pro139Leu	missense
NC_000007.14:g.44243526G>A
NC_000007.13:g.44283125G>A
NG_029407.1:g.87106C>T

... more HGVS ... less HGVS

Protein change

P139L

Other names

Canonical SPDI

NC_000007.14:44243525:G:A

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: CA367366362 OMIM: 607707.0003 dbSNP: rs1554389088 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.
CAMK2B		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	729	758

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, autosomal dominant 54	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jan 22, 2024	RCV000516163.17
Intellectual disability	Pathogenic (1)	no assertion criteria provided	Jul 3, 2017	RCV000577890.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2017	RCV000623203.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 15, 2022	RCV001571738.10
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814167.2
Agitation Apnea Dystonic disorder Global developmental delay Hyperventilation Microcephaly	Likely pathogenic (1)	no assertion criteria provided	-	RCV001003964.2

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 (Oct 21, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001796261.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (impairment of neuronal migration in murine models) (Kury et al., 2017); Not observed in large population cohorts (gnomAD); … (more) Published functional studies demonstrate a damaging effect (impairment of neuronal migration in murine models) (Kury et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 29100089, 30842224, 29100083, 30577886, 31036916, 30979967, 32875707, 31785789) (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 54 Affected status: yes Allele origin: germline	3billion Accession: SCV002058965.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:29100089 PMID:29100089 Comment: The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29100089, PS4_M). In silico tool predictions suggest damaging effect of the … (more) The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29100089, PS4_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100089, , PS2_S). . Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal facial shape (present) , Frontal bossing (present) , Generalized hypotonia (present) , Global developmental delay (present)
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 54 Affected status: yes Allele origin: germline	DASA Accession: SCV002097279.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (2) PubMed: 29100089‚ 32875707 Comment: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29100089) - PS3_moderate. The c.416C>T;p.(Pro139Leu) … (more) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29100089) - PS3_moderate. The c.416C>T;p.(Pro139Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 430922; PMID: 32875707; 29100089) - PS4. This variant is not present in population databases (rs1554389088, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32875707; 29100089) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Sep 15, 2022)	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: SCV002206002.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 29100089‚ 30842224‚ 31036916 Comment: ClinVar contains an entry for this variant (Variation ID: 430922). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089, 30842224, 31036916). … (more) ClinVar contains an entry for this variant (Variation ID: 430922). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089, 30842224, 31036916). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the CAMK2B protein (p.Pro139Leu). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089). (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 54 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002576438.3 First in ClinVar: Oct 01, 2022 Last updated: Mar 10, 2024	Comment: Criteria applied: PS4, PS2_VSTR, PS3_MOD, PM2_SUP, PP2 Clinical Features: Microcephaly (present) , Autism (present) , Optic atrophy (present) , Hypotonia (present) , Severe global developmental delay (present) Sex: female
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 54 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820184.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023	Comment: The missense variant p.P139L in CAMK2B (NM_001220.4) hasbeen previously reported in an affected patient (Kury et al,2017). It has been classified as Likely Pathogenic in … (more) The missense variant p.P139L in CAMK2B (NM_001220.4) hasbeen previously reported in an affected patient (Kury et al,2017). It has been classified as Likely Pathogenic in the ClinVar database. The p.P139L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P139L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 139 of CAMK2B is conserved in all mammalian species. The nucleotide c.416 in CAMK2B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Global developmental delay (present) , Seizure (present) , Microcephaly (present) , Visual loss (present) , Hearing impairment (present)
Pathogenic (Feb 21, 2023)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Intellectual disability, autosomal dominant 54 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045894.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Abnormal visual fixation (present) , Congenital blindness (present)
Pathogenic (Sep 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 54 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746610.1 First in ClinVar: Dec 11, 2017 Last updated: Dec 11, 2017	Publications: PubMed (1) PubMed: 29100089 Comment: This variant has been reported in PMID:29100089 (individual 20). Number of individuals with the variant: 1 Clinical Features: Sleep disturbance (present) , Short stature (present) , Reduced visual acuity (present) , Profound global developmental delay (present) , Neonatal respiratory distress (present) , Muscular … (more) Sleep disturbance (present) , Short stature (present) , Reduced visual acuity (present) , Profound global developmental delay (present) , Neonatal respiratory distress (present) , Muscular hypotonia (present) , Microcephaly (present) , Hyperkinesis (present) , Feeding difficulties (present) , Failure to thrive (present) , Dyskinesia (present) , Constipation (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Mexican; Puerto Rican; Mixed European Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2017-09-11 Testing laboratory interpretation: Pathogenic
Pathogenic (Oct 12, 2017)	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: SCV000742890.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: de novo	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755627.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jul 03, 2017)	no assertion criteria provided Method: research	Intellectual disability Affected status: yes Allele origin: de novo	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV000583489.1 First in ClinVar: Jan 27, 2018 Last updated: Jan 27, 2018	Publications: PubMed (1) PubMed: 29100089 Observation 1: Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormality of movement … (more) Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormality of movement (present) , Abnormal emotion/affect behavior (present) , Growth abnormality (present) , Abnormality of the eye (present) , Abnormality of the face (present) , Microcephaly (present) , Abnormality of the digestive system (present) (less) Observation 2: Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormal emotion/affect behavior … (more) Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormal emotion/affect behavior (present) , Growth abnormality (present) , Abnormality of the eye (present) , Abnormality of the face (present) , Abnormality of the digestive system (present) (less) Observation 3: Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormality of movement … (more) Global developmental delay (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Muscular hypotonia (present) , Abnormality of movement (present) , Abnormal emotion/affect behavior (present) , Growth abnormality (present) , Abnormality of the eye (present) , Abnormality of the face (present) , Microcephaly (present) , Abnormality of the digestive system (present) (less) Observation 4: Tissue: Brain Result: pathogenic
Likely pathogenic (Feb 05, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability, autosomal dominant 54 Affected status: yes Allele origin: germline	Gene Discovery Core-Manton Center, Boston Children's Hospital Accession: SCV000930676.1 First in ClinVar: Aug 14, 2019 Last updated: Aug 14, 2019	Publications: PubMed (1) PubMed: 29100089
Likely pathogenic (-)	no assertion criteria provided Method: research	Global developmental delay Dystonic disorder Hyperventilation Agitation Microcephaly Apnea Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161973.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: female
Pathogenic (Apr 28, 2022)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 54 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000612158.2 First in ClinVar: Dec 11, 2017 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 29100089 Comment on evidence: In 4 unrelated patients (individuals 17, 18, 19, and 2) with autosomal dominant intellectual developmental disorder-54 (MRD54; 617799), Kury et al. (2017) identified a de … (more) In 4 unrelated patients (individuals 17, 18, 19, and 2) with autosomal dominant intellectual developmental disorder-54 (MRD54; 617799), Kury et al. (2017) identified a de novo heterozygous c.416C-T transition (c.416C-T, NM_172079.2) in exon 7 of the CAMK2B gene, resulting in a pro139-to-leu (P139L) substitution at a conserved residue in the protein kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in available public databases. (less)
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Comment:

Published functional studies demonstrate a damaging effect (impairment of neuronal migration in murine models) (Kury et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 29100089, 30842224, 29100083, 30577886, 31036916, 30979967, 32875707, 31785789)

Comment:

The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29100089, PS4_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100089, , PS2_S). . Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29100089) - PS3_moderate. The c.416C>T;p.(Pro139Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 430922; PMID: 32875707; 29100089) - PS4. This variant is not present in population databases (rs1554389088, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32875707; 29100089) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

ClinVar contains an entry for this variant (Variation ID: 430922). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089, 30842224, 31036916). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the CAMK2B protein (p.Pro139Leu). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089).

Comment:

The missense variant p.P139L in CAMK2B (NM_001220.4) hasbeen previously reported in an affected patient (Kury et al,2017). It has been classified as Likely Pathogenic in the ClinVar database. The p.P139L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P139L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 139 of CAMK2B is conserved in all mammalian species. The nucleotide c.416 in CAMK2B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely 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
Severe intellectual disability, absence of language, epilepsy, microcephaly and progressive cerebellar atrophy related to the recurrent de novo variant p.(P139L) of the CAMK2B gene: A case report and brief review.	Rizzi S	American journal of medical genetics. Part A	2020	PMID: 32875707
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants.	Lecoquierre F	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036916
Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.	Iwama K	Journal of medical genetics	2019	PMID: 30842224
De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.	Küry S	American journal of human genetics	2017	PMID: 29100089

Text-mined citations for rs1554389088 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001220.5(CAMK2B):c.416C>T (p.Pro139Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554389088 ...