ClinVar Miner

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

dbSNP: rs869312840
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Total submissions: 19
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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)
Invitae 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).
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 Program, 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

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