VCV000180229.47 - ClinVar

NM_006766.5(KAT6A):c.3385C>T (p.Arg1129Ter)

Germline

Classification

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.

(15)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006766.5(KAT6A):c.3385C>T (p.Arg1129Ter)

Variation ID: 180229 Accession: VCV000180229.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.21 8: 41934835 (GRCh38) [ NCBI UCSC ] 8: 41792353 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 28, 2015	Oct 20, 2024	Nov 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006766.5:c.3385C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006757.2:p.Arg1129Ter	nonsense
NC_000008.11:g.41934835G>A
NC_000008.10:g.41792353G>A
NG_042093.1:g.122192C>T

Protein change

R1129*

Other names

NM_001099412.1:c.3385C>T

Canonical SPDI

NC_000008.11:41934834:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA004190 OMIM: 601408.0001 dbSNP: rs786200960 VarSome

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
Gene	OMIM	HI score Help 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.
KAT6A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1478	1535

Conditions - Germline

Condition Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 28, 2016	RCV000623870.4
Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Nov 10, 2023	RCV000167546.18
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Sep 7, 2022	RCV001091600.29

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 Help 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.
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102699.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468981.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Jun 28, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741647.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (1) PubMed: 17374998 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Apraxia (present) , Abnormal heart morphology (present) , Hypoplasia of the corpus callosum (present) , Patent foramen ovale (present) , … (more) Global developmental delay (present) , Apraxia (present) , Abnormal heart morphology (present) , Hypoplasia of the corpus callosum (present) , Patent foramen ovale (present) , Ventricular septal defect (present) , Atrial septal defect (present) , Sparse scalp hair (present) , Narrow forehead (present) , Midface retrusion (present) , Facial asymmetry (present) , Posteriorly rotated ears (present) , Protruding ear (present) , Narrow palate (present) , Thin upper lip vermilion (present) , Narrow mouth (present) , Micrognathia (present) , Prominent nasal tip (present) , Wide intermamillary distance (present) , Long fingers (present) , Abnormality of the palmar creases (present) , Overlapping toe (present) , Broad-based gait (present) , Gait imbalance (present) (less) Sex: female Ethnicity/Population group: Caucasian/Norwegian/Polish/German
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Affected status: yes Allele origin: de novo	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003918910.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026464.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PM2_SUP, PS3
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Affected status: yes Allele origin: de novo	DECIPHERD-UDD, Universidad del Desarrollo Accession: SCV004171018.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 38177409 Clinical Features: Failure to thrive in infancy (present) , Hypertonia (present) , Autistic behavior (present) , Global developmental delay (present) , Cognitive impairment (present) , Cerebral white … (more) Failure to thrive in infancy (present) , Hypertonia (present) , Autistic behavior (present) , Global developmental delay (present) , Cognitive impairment (present) , Cerebral white matter hypoplasia (present) , Partial agenesis of the corpus callosum (present) , Autistic behavior (present) , Abnormal facial shape (present) , Microcephaly (present) , Strabismus (present) , Prolonged QT interval (present) , Gastroesophageal reflux (present) , Gastrointestinal dysmotility (present) , Intestinal pseudo-obstruction (present) , Short foot (present) , Small hand (present) , Limited knee extension (present) , Arterial thrombosis (present) (less)
Pathogenic (Mar 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003820852.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Sep 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440699.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 25728775‚ 32041641 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180229). This premature translational stop signal has been observed in individual(s) with KAT6A-related conditions (PMID: 25728775, 32041641). In at least one individual the variant was observed to be de novo. This sequence change creates a premature translational stop signal (p.Arg1129*) in the KAT6A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 876 amino acid(s) of the KAT6A protein. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769367.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 25728775‚ 25728777‚ 30245513 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Arboleda-Tham syndrome (MIM# 616268). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - 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 at least 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) 0601 - Variant affects the well-established functional transactivation domain, which is essential for normal protein function (PMID: 25728777). (SP) 0701 - Other downstream protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple affected individuals, including de novo events, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 25728775, 30245513). (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 (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247733.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Jan 15, 2015)	no assertion criteria provided Method: clinical testing	KAT6A syndrome Affected status: yes Allele origin: de novo	UCLA Clinical Genomics Center, UCLA Accession: SCV000196747.1 First in ClinVar: May 09, 2015 Last updated: May 09, 2015 Comment: Clinical Exome	Publications: PubMed (1) PubMed: 25728775 Number of individuals with the variant: 3 Clinical Features: developmental delay, microcephaly (present) Family history: yes
Pathogenic (Mar 05, 2015)	no assertion criteria provided Method: literature only	ARBOLEDA-THAM SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000218421.4 First in ClinVar: Mar 28, 2015 Last updated: May 16, 2021	Publications: PubMed (1) PubMed: 25728775 Comment on evidence: In 3 unrelated children (1-II-1, 2-II-2, 4-II-1) with Arboleda-Tham syndrome (ARTHS; 616268), Arboleda et al. (2015) identified a de novo heterozygous c.3385C-T transition in the … (more) In 3 unrelated children (1-II-1, 2-II-2, 4-II-1) with Arboleda-Tham syndrome (ARTHS; 616268), Arboleda et al. (2015) identified a de novo heterozygous c.3385C-T transition in the last exon of the KAT6A gene, resulting in an arg1129-to-ter (R1129X) substitution, predicted to cause truncation within the acidic domain of the protein, thus leaving the HAT domain intact. The mutation, which occurred at a CpG base, was found by exome sequencing and confirmed by Sanger sequencing. It was not present in the Exome Variant Server or Exome Aggregation Consortium databases or in 1,815 in-house clinical exomes. Studies of patient cells showed that the mutation did not cause nonsense-mediated mRNA decay. Western blot analysis of cells derived from 1 patient showed changes in histone acetylation compared to controls, with a decrease in H3K9 acetylation and an increase in H3K18 acetylation. Although there were no changes in p53 (TP53; 191170) acetylation, there were significant changes in gene expression of genes involved in downstream p53 signaling. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956450.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	KAT6A syndrome Affected status: yes Allele origin: de novo	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427760.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968338.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180229). This premature translational stop signal has been observed in individual(s) with KAT6A-related conditions (PMID: 25728775, 32041641). In at least one individual the variant was observed to be de novo. This sequence change creates a premature translational stop signal (p.Arg1129*) in the KAT6A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 876 amino acid(s) of the KAT6A protein.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Arboleda-Tham syndrome (MIM# 616268). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - 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 at least 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) 0601 - Variant affects the well-established functional transactivation domain, which is essential for normal protein function (PMID: 25728777). (SP) 0701 - Other downstream protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple affected individuals, including de novo events, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 25728775, 30245513). (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

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile.	Poli MC	European journal of human genetics : EJHG	2024	PMID: 38177409
Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum.	Urreizti R	Orphanet journal of rare diseases	2020	PMID: 32041641
KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.	Kennedy J	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30245513
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.	Tham E	American journal of human genetics	2015	PMID: 25728777
De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.	Arboleda VA	American journal of human genetics	2015	PMID: 25728775
The diverse biological roles of MYST histone acetyltransferase family proteins.	Thomas T	Cell cycle (Georgetown, Tex.)	2007	PMID: 17374998

Text-mined citations for rs786200960 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_006766.5(KAT6A):c.3385C>T (p.Arg1129Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786200960 ...