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

dbSNP: rs869312840

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000210367	SCV000266476	pathogenic	not provided	2022-06-09	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210367	SCV000937376	pathogenic	not provided	2019-08-31	criteria provided, single submitter	clinical testing	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.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000210367	SCV001334384	pathogenic	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000239482	SCV001428844	pathogenic	Okur-Chung neurodevelopmental syndrome	2023-03-13	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3-SUP, PS4, PM2_SUP, PP2
Ambry Genetics	RCV001267578	SCV001445760	pathogenic	Inborn genetic diseases	2022-03-07	criteria provided, single submitter	clinical testing	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000210367	SCV001449737	pathogenic	not provided	2019-04-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000239482	SCV001522695	pathogenic	Okur-Chung neurodevelopmental syndrome	2020-07-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420211	SCV001622631	likely pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PVS1_strong;PM2_supporting;PM6_moderate
3billion	RCV000239482	SCV002318613	pathogenic	Okur-Chung neurodevelopmental syndrome	2022-03-22	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000239482	SCV002557349	pathogenic	Okur-Chung neurodevelopmental syndrome	2022-02-02	criteria provided, single submitter	clinical testing	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
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273990	SCV002559125	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV000239482	SCV002577681	pathogenic	Okur-Chung neurodevelopmental syndrome	2022-10-04	criteria provided, single submitter	clinical testing	PS4;PM1;PM2_supporting;PM6;PP2;PP3
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000239482	SCV003804094	likely pathogenic	Okur-Chung neurodevelopmental syndrome	2022-01-07	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000239482	SCV003935003	pathogenic	Okur-Chung neurodevelopmental syndrome	2023-06-23	criteria provided, single submitter	clinical testing	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).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000210367	SCV005196633	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000239482	SCV005417473	pathogenic	Okur-Chung neurodevelopmental syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PM6_Strong+PM1+PP2
OMIM	RCV000239482	SCV000297874	pathogenic	Okur-Chung neurodevelopmental syndrome	2019-02-20	no assertion criteria provided	literature only
GenomeConnect - Simons Searchlight	RCV000239482	SCV001443593	pathogenic	Okur-Chung neurodevelopmental syndrome	2019-02-08	no assertion criteria provided	provider interpretation	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.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000239482	SCV001450689	pathogenic	Okur-Chung neurodevelopmental syndrome	2020-04-27	no assertion criteria provided	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV000239482	SCV004100826	pathogenic	Okur-Chung neurodevelopmental syndrome	2020-11-27	no assertion criteria provided	clinical testing	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]
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000239482	SCV004101127	pathogenic	Okur-Chung neurodevelopmental syndrome	2023-11-02	no assertion criteria provided	clinical testing