ClinVar Genomic variation as it relates to human health
NM_012330.4(KAT6B):c.3769_3772del (p.Lys1258fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012330.4(KAT6B):c.3769_3772del (p.Lys1258fs)
Variation ID: 30530 Accession: VCV000030530.17
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 10q22.2 10: 75028589-75028592 (GRCh38) [ NCBI UCSC ] 10: 76788351-76788354 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 1, 2024 Jun 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012330.4:c.3769_3772del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036462.2:p.Lys1258fs frameshift NM_001256468.2:c.3220_3223del NP_001243397.1:p.Lys1075fs frameshift NM_001256469.2:c.2893_2896del NP_001243398.1:p.Lys966fs frameshift NM_001370132.1:c.2731_2734del NP_001357061.1:p.Lys912fs frameshift NM_001370133.1:c.2080_2083del NP_001357062.1:p.Lys695fs frameshift NM_001370134.1:c.1684_1687del NP_001357063.1:p.Lys563fs frameshift NM_001370135.1:c.1426_1429del NP_001357064.1:p.Lys477fs frameshift NM_001370136.1:c.3769_3772del NP_001357065.1:p.Lys1258fs frameshift NM_001370137.1:c.3769_3772del NP_001357066.1:p.Lys1258fs frameshift NM_001370138.1:c.3220_3223del NP_001357067.1:p.Lys1075fs frameshift NM_001370139.1:c.2893_2896del NP_001357068.1:p.Lys966fs frameshift NM_001370140.1:c.2893_2896del NP_001357069.1:p.Lys966fs frameshift NM_001370141.1:c.2893_2896del NP_001357070.1:p.Lys966fs frameshift NM_001370142.1:c.2893_2896del NP_001357071.1:p.Lys966fs frameshift NM_001370143.1:c.2704_2707del NP_001357072.1:p.Lys903fs frameshift NM_001370144.1:c.2704_2707del NP_001357073.1:p.Lys903fs frameshift NM_012330.3:c.3769_3772del NC_000010.11:g.75028589TCTA[1] NC_000010.10:g.76788347TCTA[1] NG_032048.1:g.207177TCTA[1] - Protein change
- K912fs, K966fs, K695fs, K903fs, K477fs, K1075fs, K1258fs, K563fs
- Other names
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- Canonical SPDI
- NC_000010.11:75028588:TCTATCTA:TCTA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KAT6B | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1241 | 1267 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 5, 2022 | RCV000023487.15 | |
not provided (1) |
no classification provided
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- | RCV000128645.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2023 | RCV001266158.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Genitopatellar syndrome
Affected status: yes
Allele origin:
de novo
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Department of Medical Genetics, Oslo University Hospital
Accession: SCV001437577.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Craniosynostosis (present)
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Pathogenic
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Genitopatellar syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001374953.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1258Glyfs*13) in the KAT6B gene. … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1258Glyfs*13) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 816 amino acid(s) of the KAT6B protein. This premature translational stop signal has been observed in individual(s) with genitopatellar syndrome (PMID: 12949978, 22265014, 25424711). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30530). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Genitopatellar syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138090.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444330.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.3769_3772delTCTA (p.K1258Gfs*13) alteration, located in exon 18 (coding exon 16) of the KAT6B gene, consists of a deletion of 4 nucleotides from position 3769 … (more)
The c.3769_3772delTCTA (p.K1258Gfs*13) alteration, located in exon 18 (coding exon 16) of the KAT6B gene, consists of a deletion of 4 nucleotides from position 3769 to 3772, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the KAT6B gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 39.3% of the protein. Premature stop codons are typically deleterious in nature. Furthermore, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with genitopatellar syndrome, including multiple cases of reported de novo occurrence (Simpson, 2012; Campeau, 2012; Gannon, 2015; Takahashi, 2020; Zhang, 2020; Tønne, 2021; Yabumoto, 2021). Functional studies of fibroblast cells from a patient with a heterozygous p.L1258Gfs*13 alteration showed a mature, but truncated KAT6B protein product. Additional studies showed a significant reduction in histone (H3 and H4) acetylation in patient fibroblasts compared to control samples, suggesting the truncated protein results in altered protein activity (Simpson, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 10, 2012)
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no assertion criteria provided
Method: literature only
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GENITOPATELLAR SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044778.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 24, 2020 |
Comment on evidence:
In an unrelated 7-month-old girl and 3-month-old boy with genitopatellar syndrome (606170), Simpson et al. (2012) identified heterozygosity for a 4-bp deletion (3768_3771delTCTA) in the … (more)
In an unrelated 7-month-old girl and 3-month-old boy with genitopatellar syndrome (606170), Simpson et al. (2012) identified heterozygosity for a 4-bp deletion (3768_3771delTCTA) in the KAT6B gene, resulting in a frameshift and premature termination (Lys1258GlyfsTer13). The mutation was not present in their unaffected parents, in the 1000 Genomes Project, or in 600 control exome profiles. Quantitative assessment of global H3/H4 acetylation of extracted histones in primary skin fibroblasts from the infant girl demonstrated a significant reduction in H3 and H4 acetylation compared to control fibroblasts. In 2 unrelated male patients with genitopatellar syndrome (606170), 1 of whom was originally reported by Lifchez et al. (2003), Campeau et al. (2012) identified heterozygosity for a de novo 4-bp deletion, which they stated as 3769_3772delTCTA, in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain (Lys1258GlyfsTer13). The mutation was not found in the patients' unaffected parents or in the Exome Variant Server. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Lee Lab(KAT6B), Baylor College of Medicine
Accession: SCV000172285.1
First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014 |
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not provided
(-)
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no classification provided
Method: literature only
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Genitopatellar syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000055891.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms. | Yabumoto M | Molecular genetics & genomic medicine | 2021 | PMID: 34519438 |
Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis. | Tønne E | European journal of human genetics : EJHG | 2021 | PMID: 33288889 |
A Japanese Patient with Genitopatellar Syndrome Transiently Presenting with Cardiac Intramural Cavity during the Neonatal Period. | Takahashi K | Case reports in genetics | 2020 | PMID: 32908725 |
Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants. | Zhang LX | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32424177 |
KAT6B Disorders. | Adam MP | - | 2020 | PMID: 23236640 |
Further delineation of the KAT6B molecular and phenotypic spectrum. | Gannon T | European journal of human genetics : EJHG | 2015 | PMID: 25424711 |
The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. | Campeau PM | Human mutation | 2012 | PMID: 22715153 |
De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. | Simpson MA | American journal of human genetics | 2012 | PMID: 22265017 |
Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. | Campeau PM | American journal of human genetics | 2012 | PMID: 22265014 |
Genitopatellar syndrome: expanding the phenotype. | Lifchez CA | American journal of medical genetics. Part A | 2003 | PMID: 12949978 |
Text-mined citations for rs199470470 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.