Submissions for variant NM_012330.4(KAT6B):c.4205_4206del (p.Ser1402fs)

dbSNP: rs199470477

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128652	SCV000322054	pathogenic	not provided	2019-10-30	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 672 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22077973, 28696035)
Ambry Genetics	RCV000623297	SCV000741447	pathogenic	Inborn genetic diseases	2016-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV000641704	SCV000763352	pathogenic	Genitopatellar syndrome	2023-02-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39001). This premature translational stop signal has been observed in individual(s) with genitopatellar syndrome or Say-Barber-Biesecker-Young-Simpson syndrome and KAT6B-related conditions (PMID: 22077973, 25424711, 28696035; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1402Cysfs*5) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 672 amino acid(s) of the KAT6B protein.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000641704	SCV001150140	pathogenic	Genitopatellar syndrome	2019-08-19	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001194640	SCV001364303	pathogenic	Genitopatellar syndrome; Blepharophimosis - intellectual disability syndrome, SBBYS type	2020-05-15	criteria provided, single submitter	research	ACMG codes: PVS1, PS2, PS4M, PM2, PP4, PP5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002054533	SCV002320877	pathogenic	Genitopatellar syndrome; Epilepsy, familial temporal lobe, 1	2022-04-04	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000641704	SCV003761291	pathogenic	Genitopatellar syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Ser1402CysfsTer5 variant in KAT6B was identified by our study in one individual with microcephaly, agenesis of the corpus callosum, and global developmental delay. Trio exome analysis showed this variant to be de novo. This variant was found to be de novo in 6 individuals with confirmed paternity and maternity (PMID: 28696035, PMID: 22077973, PMID: 25424711, SCV001150140.1, SCV001364303.1). This variant is assumed de novo in 2 individuals, but maternity and paternity have not been confirmed (PMID: 25424711, PMID: 22077973). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 39001) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies.This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1402 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the KAT6B gene is an established disease mechanism in autosomal dominant genitopatellar syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant genitopatellar syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015).
GeneReviews	RCV000032258	SCV000055892	not provided	Blepharophimosis - intellectual disability syndrome, SBBYS type		no assertion provided	literature only
Lee Lab(KAT6B), Baylor College of Medicine	RCV000128652	SCV000172292	not provided	not provided		no assertion provided	not provided