VCV000694682.36 - ClinVar

NM_013275.6(ANKRD11):c.1372C>T (p.Arg458Ter)

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.

(7)

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.1372C>T (p.Arg458Ter)

Variation ID: 694682 Accession: VCV000694682.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89285170 (GRCh38) [ NCBI UCSC ] 16: 89351578 (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	Nov 30, 2019	Oct 20, 2024	Mar 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_013275.6:c.1372C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037407.4:p.Arg458Ter	nonsense
NM_001256182.2:c.1372C>T	NP_001243111.1:p.Arg458Ter	nonsense
NM_001256183.1:c.1372C>T
NM_001256183.2:c.1372C>T	NP_001243112.1:p.Arg458Ter	nonsense
NC_000016.10:g.89285170G>A
NC_000016.9:g.89351578G>A
NG_032003.2:g.210392C>T

... more HGVS ... less HGVS

Protein change

R458*

Other names

Canonical SPDI

NC_000016.10:89285169: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

dbSNP: rs900492387 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 (4)	criteria provided, multiple submitters, no conflicts	Mar 8, 2023	RCV000856736.10
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 17, 2021	RCV001569459.26

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: unknown	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV000999283.1 First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019	Number of individuals with the variant: 1 Clinical Features: Short middle phalanx of the 5th finger (present) , Global developmental delay (present) , Coxa plana (present) , Autistic disorder of childhood onset (present) , … (more) Short middle phalanx of the 5th finger (present) , Global developmental delay (present) , Coxa plana (present) , Autistic disorder of childhood onset (present) , Long palpebral fissure (present) , Long philtrum (present) , Slender finger (present) , Clinodactyly (present) (less)
Pathogenic (Nov 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: paternal	Daryl Scott Lab, Baylor College of Medicine Accession: SCV001448622.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Publications: PubMed (1) PubMed: 33461977 Number of individuals with the variant: 1
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: SCV002097354.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Number of individuals with the variant: 1 Sex: male
Pathogenic (Dec 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001793541.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: Nonsense 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) Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 30202406) (less)
Pathogenic (Nov 03, 2021)	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: SCV002010609.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Mar 08, 2023)	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: SCV002229446.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 30202406‚ 35682590‚ 21782149‚ 25125236‚ 25413698‚ 25652421 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 694682). 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: 694682). This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 30202406, 35682590). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg458*) 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 01, 2021)	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: SCV001961635.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 30202406)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 694682). This premature translational stop signal has been observed in individuals with KBG syndrome (PMID: 30202406, 35682590). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg458*) 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).

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
Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.	Scott TM	Journal of medical genetics	2022	PMID: 33461977
Applying filtration steps to interpret the results of whole-exome sequencing in a consanguineous population to achieve a high detection rate.	Alfares AA	International journal of health sciences	2018	PMID: 30202406
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 rs900492387 ...

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.1372C>T (p.Arg458Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs900492387 ...