Submissions for variant NM_012330.4(KAT6B):c.3172C>T (p.Arg1058Ter)

dbSNP: rs1554843815

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627378	SCV000748372	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing	The R1058X variant in the KAT6B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1058X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R1058X as a pathogenic variant.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV001264410	SCV001441610	pathogenic	Genitopatellar syndrome; Blepharophimosis - intellectual disability syndrome, SBBYS type		criteria provided, single submitter	clinical testing	ACMG classification: pathogenic (class 5: PVS1, PS2, PM2, PP5)
Baylor Genetics	RCV001331762	SCV001523873	pathogenic	Blepharophimosis - intellectual disability syndrome, SBBYS type	2019-01-16	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382788	SCV001581693	pathogenic	Genitopatellar syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with KAT6B-related conditions. ClinVar contains an entry for this variant (Variation ID: 523902). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the KAT6B protein in which other variant(s) (p.Arg1797*) have been determined to be pathogenic (PMID: 22077973, 23436491). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg1058*) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1016 amino acid(s) of the KAT6B protein. This variant is not present in population databases (gnomAD no frequency).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001331762	SCV002767343	pathogenic	Blepharophimosis - intellectual disability syndrome, SBBYS type	2021-05-06	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: 0103 - Loss- and gain of function are mechanisms of disease in this gene and are associated with SBBYSS (MIM#603736) and Genitopatellar syndrome (GPS) (MIM#606170), respectively. NMD-predicted variants have a loss of function mechanism, and cause SBBYSS. Protein truncating variants (PTVs) found in the last exon have been reported in individuals with both conditions. PTVs found in the proximal end of the final exon have been reported in individuals with GPS, and are suspected of having a gain of function mechanism. Individuals with PTVs in the terminal end of the final exon have SBBYSS (PMID: 22715153, PMID: 32424177). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variant have been reported many times as pathogenic, and are consistently reported in individuals with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (Decipher, PMID: 32424177). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (ClinVar), and identified as de novo in two individuals with SBBYSS (PMID: 32424177). (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
PreventionGenetics, part of Exact Sciences	RCV004527691	SCV004103818	pathogenic	KAT6B-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	The KAT6B c.3172C>T variant is predicted to result in premature protein termination (p.Arg1058*). This variant has been reported in individuals with Say-Barber-Bieseker-Young-Simpson syndrome (Table S1, Zhang et al 2020. PubMed ID: 32424177). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in KAT6B are expected to be pathogenic. This variant is interpreted as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001331762	SCV004812125	pathogenic	Blepharophimosis - intellectual disability syndrome, SBBYS type	2024-03-27	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2,PM2_SUP