VCV000522794.16 - ClinVar

NM_003718.5(CDK13):c.2524A>G (p.Asn842Asp)

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/Likely 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_003718.5(CDK13):c.2524A>G (p.Asn842Asp)

Variation ID: 522794 Accession: VCV000522794.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p14.1 7: 40046006 (GRCh38) [ NCBI UCSC ] 7: 40085605 (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	Apr 29, 2018	Oct 13, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003718.5:c.2524A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003709.3:p.Asn842Asp	missense
NM_031267.3:c.2524A>G	NP_112557.2:p.Asn842Asp	missense
NC_000007.14:g.40046006A>G
NC_000007.13:g.40085605A>G
NG_052965.1:g.100647A>G

... more HGVS ... less HGVS

Protein change

N842D

Other names

Canonical SPDI

NC_000007.14:40046005:A:G

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: CA367280374 OMIM: 603309.0005 dbSNP: rs1554333853 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.
CDK13		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	721	848

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.
Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 27, 2022	RCV000625958.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV001383184.8

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 (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002072584.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Publications: PubMed (1) PubMed: 35904974 Number of individuals with the variant: 1
Likely pathogenic (Dec 08, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746556.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018	Publications: PubMed (1) PubMed: 28807008 Comment: This variant has been reported in PMID:28807008 (individual 1001). Number of individuals with the variant: 1 Clinical Features: Wide intermamillary distance (present) , Ventriculomegaly (present) , Upper airway obstruction (present) , Tapered finger (present) , Talipes equinovarus (present) , Small hand (present) , … (more) Wide intermamillary distance (present) , Ventriculomegaly (present) , Upper airway obstruction (present) , Tapered finger (present) , Talipes equinovarus (present) , Small hand (present) , Small for gestational age (present) , Skin dimples (present) , Short nose (present) , Short nail (present) , Short foot (present) , Respiratory insufficiency due to muscle weakness (present) , Relative macrocephaly (present) , Pulmonic stenosis (present) , Prominent nasal bridge (present) , Prominent glabella (present) , Prominent fingertip pads (present) , Prominent coccyx (present) , Primary Caesarian section (present) , Poor head control (present) , Polyhydramnios (present) , Overfolding of the superior helices (present) , Optic nerve hypoplasia (present) , Opisthotonus (present) , Neonatal respiratory distress (present) , Neonatal asphyxia (present) , Narrow mouth (present) , Multiple suture craniosynostosis (present) , Micrognathia (present) , Low-set ears (present) , Large fleshy ears (present) , Hypoplastic coccygeal vertebrae (present) , Hypertonia (present) , Hypertelorism (present) , Highly arched eyebrow (present) , High, narrow palate (present) , Global developmental delay (present) , Focal white matter lesions (present) , Flat face (present) , Epicanthus (present) , Duplicated collecting system (present) , Dolichocephaly (present) , Clitoral hypertrophy (present) , Clinodactyly of the 5th finger (present) , Cerebral white matter atrophy (present) , Caesarian section (present) , Birth length less than 3rd percentile (present) , Atrial septal defect (present) , Anteverted nares (present) , Achilles tendon contracture (present) , Absent/hypoplastic coccyx (present) , Absent speech (present) , Absent proximal finger flexion creases (present) , Abnormal delivery (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Mexican Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-12-08 Testing laboratory interpretation: Likely pathogenic
Likely pathogenic (May 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Affected status: yes Allele origin: de novo	Department of Medical Genetics, Oslo University Hospital Accession: SCV001437574.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Number of individuals with the variant: 1 Clinical Features: Craniosynostosis (present)
Pathogenic (Apr 01, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005370543.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28807008, 29021403, 29222009, 27479907) (less)
Pathogenic (Apr 01, 2020)	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: SCV001582256.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 27479907‚ 28554332‚ 28807008‚ 29021403 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn842 amino acid residue in CDK13. Other variant(s) that disrupt this … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn842 amino acid residue in CDK13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27479907, 28554332, 28807008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with CDK13-related disease (PMID: 28807008, 29021403). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522794). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 842 of the CDK13 protein (p.Asn842Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. (less)
Pathogenic (Feb 15, 2024)	no assertion criteria provided Method: literature only	CONGENITAL HEART DEFECTS, DYSMORPHIC FACIAL FEATURES, AND INTELLECTUAL DEVELOPMENTAL DISORDER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000680088.2 First in ClinVar: Feb 05, 2018 Last updated: Mar 10, 2024	Publications: PubMed (2) PubMed: 28807008‚ 29021403 Comment on evidence: In a 2-year-old girl (patient 1001) with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Bostwick et al. (2017) identified a … (more) In a 2-year-old girl (patient 1001) with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Bostwick et al. (2017) identified a heterozygous de novo c.2524A-G transversion in the CDK13 gene that resulted in an asn842-to-asp (N842D) substitution. In a 10-year-old girl (patient 12) with CHDFIDD, Hamilton et al. (2018) identified a de novo heterozygous mutation in the CDK13 gene, resulting in an asn842-to-asp (N842D) substitution at a highly conserved residue in the protein kinase domain. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the variant would result in altered catalytic function with a dominant-negative effect. (less)
not provided (-)	no classification provided Method: literature only	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001370886.2 First in ClinVar: Jul 16, 2020 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 30702837 BookShelf: NBK536784 BookShelf: NBK536784

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28807008, 29021403, 29222009, 27479907)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn842 amino acid residue in CDK13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27479907, 28554332, 28807008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with CDK13-related disease (PMID: 28807008, 29021403). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522794). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 842 of the CDK13 protein (p.Asn842Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid.

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
Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data.	Hardcastle A	American journal of medical genetics. Part A	2022	PMID: 35904974
CDK13-Related Disorder.	Adam MP	-	2019	PMID: 30702837
Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability.	Hamilton MJ	Journal of medical genetics	2018	PMID: 29021403
Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.	Bostwick BL	Genome medicine	2017	PMID: 28807008
Genomic diagnosis for children with intellectual disability and/or developmental delay.	Bowling KM	Genome medicine	2017	PMID: 28554332
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.	Sifrim A	Nature genetics	2016	PMID: 27479907

Text-mined citations for rs1554333853 ...

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_003718.5(CDK13):c.2524A>G (p.Asn842Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554333853 ...