VCV000140472.9 - ClinVar

NM_012330.4(KAT6B):c.3788_3789del (p.Lys1263fs)

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.

(5)

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_012330.4(KAT6B):c.3788_3789del (p.Lys1263fs)

Variation ID: 140472 Accession: VCV000140472.9

Type and length

Deletion, 2 bp

Location

Cytogenetic: 10q22.2 10: 75028611-75028612 (GRCh38) [ NCBI UCSC ] 10: 76788369-76788370 (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	Jul 23, 2014	Feb 14, 2024	Jul 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_012330.4:c.3788_3789del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036462.2:p.Lys1263fs	frameshift
NM_001256468.2:c.3239_3240del	NP_001243397.1:p.Lys1080fs	frameshift
NM_001256469.2:c.2912_2913del	NP_001243398.1:p.Lys971fs	frameshift
NM_001370132.1:c.2750_2751del	NP_001357061.1:p.Lys917fs	frameshift
NM_001370133.1:c.2099_2100del	NP_001357062.1:p.Lys700fs	frameshift
NM_001370134.1:c.1703_1704del	NP_001357063.1:p.Lys568fs	frameshift
NM_001370135.1:c.1445_1446del	NP_001357064.1:p.Lys482fs	frameshift
NM_001370136.1:c.3788_3789del	NP_001357065.1:p.Lys1263fs	frameshift
NM_001370137.1:c.3788_3789del	NP_001357066.1:p.Lys1263fs	frameshift
NM_001370138.1:c.3239_3240del	NP_001357067.1:p.Lys1080fs	frameshift
NM_001370139.1:c.2912_2913del	NP_001357068.1:p.Lys971fs	frameshift
NM_001370140.1:c.2912_2913del	NP_001357069.1:p.Lys971fs	frameshift
NM_001370141.1:c.2912_2913del	NP_001357070.1:p.Lys971fs	frameshift
NM_001370142.1:c.2912_2913del	NP_001357071.1:p.Lys971fs	frameshift
NM_001370143.1:c.2723_2724del	NP_001357072.1:p.Lys908fs	frameshift
NM_001370144.1:c.2723_2724del	NP_001357073.1:p.Lys908fs	frameshift
NC_000010.11:g.75028612_75028613del
NC_000010.10:g.76788370_76788371del
NG_032048.1:g.207200_207201del

... more HGVS ... less HGVS

Protein change

K482fs, K908fs, K971fs, K1080fs, K1263fs, K568fs, K700fs, K917fs

Other names

Canonical SPDI

NC_000010.11:75028610:AAA: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: CA129315 OMIM: 605880.0007 dbSNP: rs199470472 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.
KAT6B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1281	1307

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.
Genitopatellar syndrome	Pathogenic (2)	criteria provided, single submitter	Jul 26, 2023	RCV000023488.9
not provided	Pathogenic (2)	criteria provided, single submitter	Mar 22, 2021	RCV000128647.3
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 4, 2018	RCV001267611.2

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 (Apr 04, 2018)	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: SCV001445793.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (3) PubMed: 23436491‚ 29226580‚ 22265014 Number of individuals with the variant: 1 Clinical Features: Hydronephrosis (present) , Laryngotracheomalacia (present) , Hypernatremia (present) , Colpocephaly (present) , Small anterior fontanelle (present) , Absent septum pellucidum (present) , Hemangioma (present) , … (more) Hydronephrosis (present) , Laryngotracheomalacia (present) , Hypernatremia (present) , Colpocephaly (present) , Small anterior fontanelle (present) , Absent septum pellucidum (present) , Hemangioma (present) , Clubfoot (present) , Pachygyria (present) , Short neck (present) , Polyhydramnios (present) , Posteriorly rotated ears (present) , Ventriculomegaly (present) , Failure to thrive (present) , Single transverse palmar crease (present) , Knee flexion contracture (present) , Muscular hypotonia (present) , Flexion contracture (present) , Anteverted nares (present) , Depressed nasal bridge (present) , Secundum atrial septal defect (present) (less) Sex: female Ethnicity/Population group: Caucasian
Pathogenic (Jul 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Genitopatellar syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441447.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22265014‚ 32424177 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 140472). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 140472). This premature translational stop signal has been observed in individual(s) with clinical features of genitopatellar syndrome (PMID: 22265014, 32424177; 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.Lys1263Argfs*7) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 811 amino acid(s) of the KAT6B protein. (less)
Pathogenic (Mar 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001772179.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021	Comment: Frameshift variant predicted to result in protein truncation, as the last 811 amino acids are replaced with 6 different amino acids; other loss-of-function variants have … (more) Frameshift variant predicted to result in protein truncation, as the last 811 amino acids are replaced with 6 different amino acids; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23436491, 32424177, 22265014, 22715153) (less)
Pathogenic (Feb 10, 2012)	no assertion criteria provided Method: literature only	GENITOPATELLAR SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044779.4 First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2020	Publications: PubMed (1) PubMed: 22265014 Comment on evidence: In a female patient with genitopatellar syndrome (606170), Campeau et al. (2012) identified heterozygosity for a de novo 2-bp deletion (3788_3789delAA) in exon 18 of … (more) In a female patient with genitopatellar syndrome (606170), Campeau et al. (2012) identified heterozygosity for a de novo 2-bp deletion (3788_3789delAA) in exon 18 of the KAT6B gene, predicted to result in premature termination and loss of the highly conserved transcription activation domain (Lys1263ArgfsTer7). The mutation was not found in the patients' unaffected parents or in the Exome Variant Server. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Lee Lab(KAT6B), Baylor College of Medicine Accession: SCV000172287.1 First in ClinVar: Jul 23, 2014 Last updated: Jul 23, 2014

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 140472). This premature translational stop signal has been observed in individual(s) with clinical features of genitopatellar syndrome (PMID: 22265014, 32424177; 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.Lys1263Argfs*7) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 811 amino acid(s) of the KAT6B protein.

Comment:

Frameshift variant predicted to result in protein truncation, as the last 811 amino acids are replaced with 6 different amino acids; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23436491, 32424177, 22265014, 22715153)

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
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
A novel truncating variant within exon 7 of KAT6B associated with features of both Say-Barber-Bieseker-Young-Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B-related disorders.	Marangi G	American journal of medical genetics. Part A	2018	PMID: 29226580
De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome.	Szakszon K	American journal of medical genetics. Part A	2013	PMID: 23436491
Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome.	Campeau PM	American journal of human genetics	2012	PMID: 22265014

Text-mined citations for rs199470472 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_012330.4(KAT6B):c.3788_3789del (p.Lys1263fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199470472 ...