VCV000266033.40 - ClinVar

NM_013275.6(ANKRD11):c.2408_2412del (p.Lys803fs)

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.

(16)

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_013275.6(ANKRD11):c.2408_2412del (p.Lys803fs)

Variation ID: 266033 Accession: VCV000266033.40

Type and length

Deletion, 5 bp

Location

Cytogenetic: 16q24.3 16: 89284130-89284134 (GRCh38) [ NCBI UCSC ] 16: 89350538-89350542 (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	Oct 21, 2016	Oct 20, 2024	Dec 12, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_013275.6:c.2408_2412del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037407.4:p.Lys803fs	frameshift
NM_013275.6:c.2408_2412delAAAAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001256182.2:c.2408_2412del	NP_001243111.1:p.Lys803fs	frameshift
NM_001256182.2:c.2408_2412delAAAAA
NM_001256183.2:c.2408_2412del	NP_001243112.1:p.Lys803fs	frameshift
NM_013275.4:c.2408_2412delAAAAA
NM_013275.5:c.2408_2412del5
NM_013275.5:c.2408_2412delAAAAA
NC_000016.10:g.89284131_89284135del
NC_000016.9:g.89350539_89350543del
NG_032003.2:g.211428_211432del

... more HGVS ... less HGVS

Protein change

K803fs

Other names

Canonical SPDI

NC_000016.10:89284129:TTTTTT:T

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: CA10588953 dbSNP: rs886039902 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.
ANKRD11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2546	2716

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.
KBG syndrome	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jul 23, 2022	RCV000256444.18
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 12, 2022	RCV000522964.19
Global developmental delay	Pathogenic (1)	criteria provided, single submitter	Jan 22, 2021	RCV001376675.4
ANKRD11-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 25, 2024	RCV004739645.1
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 28, 2022	RCV002519008.6

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 (Mar 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618448.2 First in ClinVar: Dec 19, 2017 Last updated: Sep 25, 2021	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27667800, 25533962, 28191890, 29224748, 28135719, 32124548) (less)
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	KBG syndrome Affected status: yes Allele origin: germline	Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano Accession: SCV002097344.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Number of individuals with the variant: 1 Sex: male
Pathogenic (Nov 01, 2022)	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: SCV002822334.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: ANKRD11: PVS1, PM2 Number of individuals with the variant: 1
Pathogenic (May 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: maternal	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000966193.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Pathogenic (Mar 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429227.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446488.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Global developmental delay (present) , Poor speech (present) , Hyperactivity (present) , Poor coordination (present) Sex: female
Pathogenic (Jan 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Global developmental delay Affected status: yes Allele origin: de novo	Institute for Human Genetics, University Hospital Essen Accession: SCV001478034.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (1) PubMed: 33955014 Observation 1: Number of individuals with the variant: 2 Observation 2:
Pathogenic (Sep 15, 2016)	criteria provided, single submitter (HA_assertions_20161101) Method: research	KBG syndrome Affected status: yes Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000323203.4 First in ClinVar: Oct 21, 2016 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Portal hypertension (present) , Macrocephaly (present) , Abnormality of cardiovascular system morphology (present) , Esophageal varix (present) , Hearing impairment (present)
Pathogenic (Jul 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002784845.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (May 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV003836673.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Dec 12, 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: SCV004026190.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1
Pathogenic (Jul 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	KBG syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000823257.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 27667800‚ 21782149‚ 25125236‚ 25413698‚ 25652421 Comment: This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). For these reasons, this variant has been classified as Pathogenic. … (more) This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266033). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys803Argfs*5) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421). (less)
Pathogenic (Sep 28, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003636019.3 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 27667800‚ 32124548‚ 33955014‚ 35682590 Comment: The c.2408_2412delAAAAA (p.K803Rfs5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 … (more) The c.2408_2412delAAAAA (p.K803Rfs5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 to 2412, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated individuals with clinical features of KBG syndrome (Parenti, 2021; Gnazzo, 2020). Additional heterozygous individuals with ANKRD11 variants have been reported in the literature (Low, 2016; Bestetti, 2022). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 25, 2024)	no assertion criteria provided Method: clinical testing	ANKRD11-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005343623.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The ANKRD11 c.2408_2412del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys803Argfs5). This variant has been reported in multiple unrelated individuals … (more) The ANKRD11 c.2408_2412del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys803Argfs5). This variant has been reported in multiple unrelated individuals with KBG syndrome (Low et al. 2016. PubMed ID: 27667800; Bianchi et al. 2017. PubMed ID: 29224748; Wright et al. 2021. PubMed ID: 33149276; Parenti et al. 2021. PubMed ID: 33955014; Marangoni et al. 2021. PubMed ID: 34906519; Digilio et al. 2021. PubMed ID: 34971082; Tal-Ben Ishay et al. 2021. PubMed ID: 35052376; Loberti et al. 2022. PubMed ID: 35861666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Apr 15, 2016)	no assertion criteria provided Method: clinical testing	KBG syndrome Affected status: yes Allele origin: de novo	Autoinflammatory diseases unit, CHU de Montpellier Accession: SCV001438088.1 First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020	Number of individuals with the variant: 2 Sex: female
Pathogenic (Sep 10, 2018)	no assertion criteria provided Method: provider interpretation	KBG syndrome Affected status: yes Allele origin: unknown	GenomeConnect - Simons Searchlight Accession: SCV001443557.1 First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020	Comment: Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially … (more) Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially reported on 2018-01-09 by GTR ID of laboratory name 506154. The reporting laboratory might also submit to ClinVar. (less) Sex: female Testing laboratory: Gene by Gene, Ltd Date variant was reported to submitter: 2018-01-09 Testing laboratory interpretation: Pathogenic
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Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27667800, 25533962, 28191890, 29224748, 28135719, 32124548)

Comment:

This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 27667800). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266033). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys803Argfs*5) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421).

Comment:

The c.2408_2412delAAAAA (p.K803Rfs*5) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 5 nucleotides from position 2408 to 2412, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated individuals with clinical features of KBG syndrome (Parenti, 2021; Gnazzo, 2020). Additional heterozygous individuals with ANKRD11 variants have been reported in the literature (Low, 2016; Bestetti, 2022). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The ANKRD11 c.2408_2412del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys803Argfs*5). This variant has been reported in multiple unrelated individuals with KBG syndrome (Low et al. 2016. PubMed ID: 27667800; Bianchi et al. 2017. PubMed ID: 29224748; Wright et al. 2021. PubMed ID: 33149276; Parenti et al. 2021. PubMed ID: 33955014; Marangoni et al. 2021. PubMed ID: 34906519; Digilio et al. 2021. PubMed ID: 34971082; Tal-Ben Ishay et al. 2021. PubMed ID: 35052376; Loberti et al. 2022. PubMed ID: 35861666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-10 and interpreted as Pathogenic. Variant was initially reported on 2018-01-09 by GTR ID of laboratory name 506154. The reporting laboratory might also submit to ClinVar.

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
Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome.	Bestetti I	International journal of molecular sciences	2022	PMID: 35682590
ANKRD11 variants: KBG syndrome and beyond.	Parenti I	Clinical genetics	2021	PMID: 33955014
KBG syndrome: Common and uncommon clinical features based on 31 new patients.	Gnazzo M	American journal of medical genetics. Part A	2020	PMID: 32124548
Clinical and genetic aspects of KBG syndrome.	Low K	American journal of medical genetics. Part A	2016	PMID: 27667800
Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.	Parenti I	Clinical genetics	2016	PMID: 25652421
Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.	Walz K	Human genetics	2015	PMID: 25413698
Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.	Ansari M	Journal of medical genetics	2014	PMID: 25125236
Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.	Sirmaci A	American journal of human genetics	2011	PMID: 21782149

Text-mined citations for rs886039902 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_013275.6(ANKRD11):c.2408_2412del (p.Lys803fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039902 ...