VCV000224790.35 - ClinVar

NM_177559.3(CSNK2A1):c.593A>G (p.Lys198Arg)

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.

(20)

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_177559.3(CSNK2A1):c.593A>G (p.Lys198Arg)

Variation ID: 224790 Accession: VCV000224790.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 492282 (GRCh38) [ NCBI UCSC ] 20: 472926 (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	Mar 8, 2017	Aug 25, 2024	Jun 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_177559.3:c.593A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_808227.1:p.Lys198Arg	missense
NM_001362770.2:c.593A>G	NP_001349699.1:p.Lys198Arg	missense
NM_001362771.2:c.593A>G	NP_001349700.1:p.Lys198Arg	missense
NM_001895.4:c.593A>G	NP_001886.1:p.Lys198Arg	missense
NM_177560.3:c.185A>G	NP_808228.1:p.Lys62Arg	missense
NC_000020.11:g.492282T>C
NC_000020.10:g.472926T>C
NG_011970.2:g.56557A>G
	P68400:p.Lys198Arg

... more HGVS ... less HGVS

Protein change

K198R, K62R

Other names

Canonical SPDI

NC_000020.11:492281:T:C

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA358394 UniProtKB: P68400#VAR_077048 OMIM: 115440.0002 dbSNP: rs869312840 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.
CSNK2A1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	188	264

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.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 9, 2022	RCV000210367.20
Okur-Chung neurodevelopmental syndrome	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Jun 23, 2023	RCV000239482.20
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 7, 2022	RCV001267578.5
See cases	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420211.3
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002273990.2

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 (Jun 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000266476.12 First in ClinVar: Apr 03, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (altered binding specificity) (Caefer et al., 2022; Werner et al., 2022); In silico analysis supports that this missense … (more) Published functional studies demonstrate a damaging effect (altered binding specificity) (Caefer et al., 2022; Werner et al., 2022); 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: 30655572, 32746809, 27048600, 29619237, 25363768, 28135719, 29383814, 28191890, 30109123, 29240241, 31060130, 28714951, 32651551, 34011629, 33726816, 31785789, 33994545, 35445078, 33944995, 35517865) (less)
Pathogenic (May 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV001334384.1 First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Pathogenic (Apr 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449737.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Jul 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522695.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622631.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PVS1_strong;PM2_supporting;PM6_moderate Clinical Features: Global developmental delay (present) , Intellectual disability (present) , Decreased response to growth hormone stimulation test (present) , Motor delay (present) , Delayed speech and … (more) Global developmental delay (present) , Intellectual disability (present) , Decreased response to growth hormone stimulation test (present) , Motor delay (present) , Delayed speech and language development (present) , Delayed myelination (present) (less) Sex: male
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002318613.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (4) PubMed: 27048600‚ 29619237‚ 29240241‚ 29383814 Comment: The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241, PS2_VS). It has … (more) The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241, PS2_VS). It has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Bulbous nose (present) , Ectropion (present) , Long eyelashes (present) , Long palpebral fissure (present) , Intellectual disability, mild (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental delay Affected status: yes Allele origin: inherited	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559125.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Oct 04, 2022)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	Okur-Chung neurodevelopmental syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV002577681.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PS4;PM1;PM2_supporting;PM6;PP2;PP3 Clinical Features: Intellectual disability (present) , Motor delay (present) , Delayed speech and language development (present) , Delayed myelination (present) , Decreased response to growth hormone stimulation … (more) Intellectual disability (present) , Motor delay (present) , Delayed speech and language development (present) , Delayed myelination (present) , Decreased response to growth hormone stimulation test (present) , Global developmental delay (present) (less) Sex: male
Likely pathogenic (Jan 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: unknown	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV003804094.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Sex: male
Pathogenic (Mar 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428844.2 First in ClinVar: Aug 17, 2020 Last updated: May 06, 2023	Comment: This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3-SUP, PS4, PM2_SUP, PP2
Pathogenic (Jun 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome (Sporadic) Affected status: yes Allele origin: de novo	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital Accession: SCV003935003.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 27048600 Comment: The heterozygous de-novo variant c.593A>G (p.Lys198Arg) has been identified in a 4months old female proband with seizures, bilateral cherry red spots, multiple episodes of apnea … (more) The heterozygous de-novo variant c.593A>G (p.Lys198Arg) has been identified in a 4months old female proband with seizures, bilateral cherry red spots, multiple episodes of apnea and cyanosis, generalized edema, dyskinetic movements of both upper limbs. This variant is identified in exon 8 which is a hotspot exon for CSNK2A1 gene (PM1_supporting). 26 pathogenic mis-sense variants have been identified in this gene (PP2_supporting). The population frequency in gnomAD (aggregated) is 0.0004% (PM2_moderate). This variant has been identified previously PMID 27048600 (PP5_very strong). (less) Age: 0-9 years Sex: female Ethnicity/Population group: South East Asian Geographic origin: India
Pathogenic (Aug 31, 2019)	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: SCV000937376.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 27048600‚ 29619237‚ 29383814‚ 29240241 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in individuals affected with Okur-Chung neurodevelopmental syndrome (PMID: 27048600, 29619237, 29383814, 29240241). ClinVar contains an entry for this variant (Variation ID: 224790). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 198 of the CSNK2A1 protein (p.Lys198Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. (less)
Pathogenic (Mar 07, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001445760.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 25363768‚ 27048600‚ 29240241‚ 29383814‚ 29619237‚ 32746809 Comment: The c.593A>G (p.K198R) alteration is located in exon 9 (coding exon 7) of the CSNK2A1 gene. This alteration results from an A to G substitution … (more) The c.593A>G (p.K198R) alteration is located in exon 9 (coding exon 7) of the CSNK2A1 gene. This alteration results from an A to G substitution at nucleotide position 593, causing the lysine (K) at amino acid position 198 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251364) total alleles studied. The p.K198R alteration is the most common alteration in Okur-Chung syndrome and has been reported as de novo in multiple patients (Iossifov, 2014; Okur, 2016; Akahira-Azuma, 2018; Owen, 2018; Chiu, 2018). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Okur-Chung neurodevelopmental syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557349.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 29383814‚ 30655572 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Okur-Chung neurodevelopmental syndrome (MIM#617062). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten individuals with Okur-Chung neurodevelopmental syndrome (MIM#617062), the majority of whom were due to de novo events (ClinVar, PMID: 29383814, 30655572). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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: SCV005196633.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Feb 20, 2019)	no assertion criteria provided Method: literature only	OKUR-CHUNG NEURODEVELOPMENTAL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000297874.2 First in ClinVar: Aug 22, 2016 Last updated: Feb 23, 2019	Publications: PubMed (4) PubMed: 27048600‚ 29240241‚ 29383814‚ 29619237 Comment on evidence: In a 4.5-year-old girl (patient 2) with Okur-Chung neurodevelopmental syndrome (OCNDS; 617062), Okur et al. (2016) identified a de novo heterozygous c.593A-G transition in the … (more) In a 4.5-year-old girl (patient 2) with Okur-Chung neurodevelopmental syndrome (OCNDS; 617062), Okur et al. (2016) identified a de novo heterozygous c.593A-G transition in the CSNK2A1 gene, resulting in a lys198-to-arg (K198R) substitution in the highly conserved activation domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 24,578 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. Chiu et al. (2018) summarized data on 16 de novo heterozygous CSNK2A1 mutations that had been reported in 22 patients with OCNDS, including their 8 newly reported patients, and found that K198R was the most common mutation, occurring in 5 patients. Four of the 8 de novo heterozygous missense mutations in CSNK2A1 identified by Owen et al. (2018) in patients with OCNDS were K198R, leading the authors to propose that this is a mutation hotspot. Akahira-Azuma et al. (2018) identified de novo heterozygosity for the recurrent K198R mutation in the CSNK2A1 gene in an 8-year-old Japanese boy with OCNDS. (less)
Pathogenic (Feb 08, 2019)	no assertion criteria provided Method: provider interpretation	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: de novo, unknown	GenomeConnect - Simons Searchlight Accession: SCV001443593.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-08 and interpreted as Pathogenic. The reporting laboratory … (more) Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-08 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Polyhydramnios (present) , Premature birth (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Strabismus (present) , Generalized hypotonia (present) … (more) Polyhydramnios (present) , Premature birth (present) , Hyperbilirubinemia (present) , Neonatal hypotonia (present) , Abnormality of vision (present) , Strabismus (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Constipation (present) , Otitis media (present) , Immunodeficiency (present) , Pneumonia (present) , Abnormality of the respiratory system (present) , Pneumonia (present) , Failure to thrive (present) , Short stature (present) , Hypothyroidism (present) , Autoimmunity (present) , Hashimoto thyroiditis (present) , Seizures (present) , Focal seizures without impairment of consciousness or awareness (present) , Abnormality of pain sensation (present) (less) Age: 0-9 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2014-12-22 Testing laboratory interpretation: Uncertain significance Observation 2: Number of individuals with the variant: 1 Clinical Features: Autistic behavior (present) , Premature birth (present) , Induced vaginal delivery (present) , Neonatal hypotonia (present) , Hearing abnormality (present) , Conductive hearing impairment (present) … (more) Autistic behavior (present) , Premature birth (present) , Induced vaginal delivery (present) , Neonatal hypotonia (present) , Hearing abnormality (present) , Conductive hearing impairment (present) , Generalized hypotonia (present) , Constipation (present) , Pneumonia (present) , Short stature (present) , Hypothyroidism (present) (less) Age: 0-9 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2016-07-29 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Autistic behavior (present) , Abnormality of vision (present) , Hypermetropia (present) , Generalized hypotonia (present) , Cerebral palsy (present) , Seizure precipitated by febrile infection … (more) Autistic behavior (present) , Abnormality of vision (present) , Hypermetropia (present) , Generalized hypotonia (present) , Cerebral palsy (present) , Seizure precipitated by febrile infection (present) , Seizures (present) , Generalized tonic-clonic seizures (present) , Constipation (present) , Otitis media (present) , Failure to thrive (present) , Short stature (present) , Hypothyroidism (present) , Allergy (present) , Allergic rhinitis (present) (less) Age: 10-19 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2017-02-06 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2018-10-17 Testing laboratory interpretation: Pathogenic Observation 5: Number of individuals with the variant: 1 Clinical Features: Caesarian section (present) , Hyperbilirubinemia (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Astigmatism (present) , … (more) Caesarian section (present) , Hyperbilirubinemia (present) , Poor suck (present) , Feeding difficulties in infancy (present) , Abnormality of vision (present) , Astigmatism (present) , Microcephaly (present) , Constipation (present) , Neoplasm (present) , Abnormality of the respiratory system (present) , Asthma (present) , Hypothyroidism (present) (less) Age: 10-19 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2019-01-09 Testing laboratory interpretation: Pathogenic
Pathogenic (Apr 27, 2020)	no assertion criteria provided Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: unknown	Service de Génétique Moléculaire, Hôpital Robert Debré Accession: SCV001450689.1 First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020
Pathogenic (Nov 27, 2020)	no assertion criteria provided Method: clinical testing	Okur-Chung neurodevelopmental syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV004100826.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Comment: The p.Lys198Arg variant in the CSNK2A1 gene has been previously reported de novo in 8 unrelated individuals with Okur-Chung neurodevelopmental syndrome (Okur et al., 2016; … (more) The p.Lys198Arg variant in the CSNK2A1 gene has been previously reported de novo in 8 unrelated individuals with Okur-Chung neurodevelopmental syndrome (Okur et al., 2016; Owen et al., 2017; Chiu et al., 2018; Akahira-Azuma et al., 2018; Nakashima et al., 2019). This variant has also been identified in 1/251361 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CSNK2A1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys198Arg variant as pathogenic for autosomal dominant Okur-Chung neurodevelopmental syndrome based on the information above. [ACMG evidence codes used: PS2; PS4; PP2] (less)
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Okur-Chung neurodevelopmental syndrome Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101127.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
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Comment:

Published functional studies demonstrate a damaging effect (altered binding specificity) (Caefer et al., 2022; Werner et al., 2022); 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: 30655572, 32746809, 27048600, 29619237, 25363768, 28135719, 29383814, 28191890, 30109123, 29240241, 31060130, 28714951, 32651551, 34011629, 33726816, 31785789, 33994545, 35445078, 33944995, 35517865)

Comment:

The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241, PS2_VS). It has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The heterozygous de-novo variant c.593A>G (p.Lys198Arg) has been identified in a 4months old female proband with seizures, bilateral cherry red spots, multiple episodes of apnea and cyanosis, generalized edema, dyskinetic movements of both upper limbs. This variant is identified in exon 8 which is a hotspot exon for CSNK2A1 gene (PM1_supporting). 26 pathogenic mis-sense variants have been identified in this gene (PP2_supporting). The population frequency in gnomAD (aggregated) is 0.0004% (PM2_moderate). This variant has been identified previously PMID 27048600 (PP5_very strong).

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in individuals affected with Okur-Chung neurodevelopmental syndrome (PMID: 27048600, 29619237, 29383814, 29240241). ClinVar contains an entry for this variant (Variation ID: 224790). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 198 of the CSNK2A1 protein (p.Lys198Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine.

Comment:

The c.593A>G (p.K198R) alteration is located in exon 9 (coding exon 7) of the CSNK2A1 gene. This alteration results from an A to G substitution at nucleotide position 593, causing the lysine (K) at amino acid position 198 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251364) total alleles studied. The p.K198R alteration is the most common alteration in Okur-Chung syndrome and has been reported as de novo in multiple patients (Iossifov, 2014; Okur, 2016; Akahira-Azuma, 2018; Owen, 2018; Chiu, 2018). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Okur-Chung neurodevelopmental syndrome (MIM#617062). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten individuals with Okur-Chung neurodevelopmental syndrome (MIM#617062), the majority of whom were due to de novo events (ClinVar, PMID: 29383814, 30655572). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-08 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.

Comment:

The p.Lys198Arg variant in the CSNK2A1 gene has been previously reported de novo in 8 unrelated individuals with Okur-Chung neurodevelopmental syndrome (Okur et al., 2016; Owen et al., 2017; Chiu et al., 2018; Akahira-Azuma et al., 2018; Nakashima et al., 2019). This variant has also been identified in 1/251361 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CSNK2A1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys198Arg variant as pathogenic for autosomal dominant Okur-Chung neurodevelopmental syndrome based on the information above. [ACMG evidence codes used: PS2; PS4; PP2]

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
Dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in one Chinese patient: a case report.	Xu S	BMC medical genetics	2020	PMID: 32746809
Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures.	Nakashima M	Journal of human genetics	2019	PMID: 30655572
Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome.	Akahira-Azuma M	Human genome variation	2018	PMID: 29619237
Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals.	Owen CI	American journal of medical genetics. Part A	2018	PMID: 29383814
Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.	Chiu ATG	Clinical genetics	2018	PMID: 29240241
De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features.	Okur V	Human genetics	2016	PMID: 27048600
The contribution of de novo coding mutations to autism spectrum disorder.	Iossifov I	Nature	2014	PMID: 25363768

Text-mined citations for rs869312840 ...

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_177559.3(CSNK2A1):c.593A>G (p.Lys198Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs869312840 ...