Submissions for variant NM_012330.4(KAT6B):c.5389C>T (p.Arg1797Ter)

dbSNP: rs199470484

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380964	SCV001579196	pathogenic	Genitopatellar syndrome	2020-04-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the KAT6B gene (p.Arg1797*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 277 amino acids of the KAT6B protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 22077973, 23436491). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50357).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786317	SCV005400435	pathogenic	KAT6B-related multiple congenital anomalies syndrome	2024-10-09	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 of function and gain of function are likely mechanisms of disease in this gene and are associated with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (MIM#603736) and genitopatellar syndrome (GPS) (MIM#606170), respectively; these two conditions are also referred to as KAT6B-related multiple congenital anomalies syndrome (MONDO:0036042) which also include individuals with intermediate phenotypes consisting of SBBYSS and GPS features. NMD-predicted variants have a loss of function mechanism, and are associated with SBBYSS. Truncating variants (PTVs) found in the last exon have been reported for both conditions, and are likely to have both a loss- and gain of function effect. PTVs found in the proximal end of the final exon have been reported in patients with GPS, while PTVs in the terminal end of the final exon have SBBYSS (PMIDs: 22715153, 32424177). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. More than five downstream truncating variants have been identified in individuals with SSBYSS or with an intermediate phenotype overlapping both SBBYSS and GPS (PMID: 32424177). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in at least three individuals with SBBYSS or an intermediate phenotype with overlapping features of SBBYSS and GPS (PMIDs: 22077973, 23436491, 28857140). It has also been classified as pathogenic by a clinical laboratory in ClinVar. (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
OMIM	RCV000043512	SCV000067382	pathogenic	Blepharophimosis - intellectual disability syndrome, SBBYS type	2013-04-01	no assertion criteria provided	literature only
Lee Lab(KAT6B), Baylor College of Medicine	RCV000128660	SCV000172300	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000043512	SCV001190853	not provided	Blepharophimosis - intellectual disability syndrome, SBBYS type		no assertion provided	literature only