ClinVar Miner

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

dbSNP: rs1554843815
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Total submissions: 7
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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

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