Submissions for variant NM_177559.3(CSNK2A1):c.468T>A (p.Asp156Glu)

dbSNP: rs1064795110

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479609	SCV000570585	likely pathogenic	not provided	2016-06-04	criteria provided, single submitter	clinical testing	The D156E variant in the CSNK2A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D156E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D156E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The D156E variant is a strong candidate for a pathogenic variant.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249615	SCV001423645	pathogenic	Okur-Chung neurodevelopmental syndrome	2018-08-08	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PM1, PM2, PM5, PP2, PP3, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Genetics and Molecular Pathology, SA Pathology	RCV001249615	SCV004175430	pathogenic	Okur-Chung neurodevelopmental syndrome	2023-01-31	criteria provided, single submitter	clinical testing	The CSNK2A1 c.468T>A variant is classified as Pathogenic (PS2, PS4_Supporting, PM5_Supporting, PM2, PP2, PP3) The CSNK2A1 c.468T>A variant is a single nucleotide change in exon 7/13 of the CSNK2A1 gene, which is predicted to change the amino acid aspartic acid at position 156 in the protein to glutamic acid. This variant has been identified as a de novo variant in this patient (PS2). The variant has been reported once in the literature with a clinical presentation of Okur-Chung neurodevelopmental syndrome (Miller et al, 2020; PMID:32371413 (PS4_Supporting). This variant is absent from population databases (PM2). This is a missense variant in a constrained gene where missense variants are a common mechanism of disease and benign variation is rare (GnomAD Z-score= 3.71) (PP2). This variant is a missense change at an amino acid residue where a different missense change p.Asp156His has been seen before (Trinh et al, 2017; PMID: 28725024) (PM5_supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs1064795110) and in the HGMD database: CM2016384. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 421395).
GenomeConnect - Simons Searchlight	RCV001249615	SCV001443594	likely pathogenic	Okur-Chung neurodevelopmental syndrome	2018-07-02	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-07-02 and interpreted as Likely Pathogenic. Variant was initially reported on 2016-06-13 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.