VCV002627026.3 - ClinVar

NM_003502.4(AXIN1):c.2167C>T (p.Arg723Ter)

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.

(2)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003502.4(AXIN1):c.2167C>T (p.Arg723Ter)

Variation ID: 2627026 Accession: VCV002627026.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 293507 (GRCh38) [ NCBI UCSC ] 16: 343507 (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 4, 2023	Apr 6, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003502.4:c.2167C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003493.1:p.Arg723Ter	nonsense
NM_181050.3:c.2167C>T	NP_851393.1:p.Arg723Ter	nonsense
NR_134879.2:n.2506C>T		non-coding transcript variant
NC_000016.10:g.293507G>A
NC_000016.9:g.343507G>A
NG_012267.1:g.63958C>T

... more HGVS ... less HGVS

Protein change

R723*

Other names

Canonical SPDI

NC_000016.10:293506: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

OMIM: 603816.0004 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.
AXIN1		-	-	GRCh38 GRCh37	96	168

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.
Craniometadiaphyseal osteosclerosis with hip dysplasia	Pathogenic (1)	no assertion criteria provided	Oct 26, 2023	RCV003388226.1
Hepatocellular carcinoma	Uncertain significance (1)	criteria provided, single submitter	Mar 25, 2024	RCV003988891.3

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.
Uncertain significance (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hepatocellular carcinoma Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805420.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Oct 26, 2023)	no assertion criteria provided Method: literature only	CRANIOMETADIAPHYSEAL OSTEOSCLEROSIS WITH HIP DYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV004099284.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Publications: PubMed (1) PubMed: 37582359 Comment on evidence: In the proband from family 2 and 2 sibs and a cousin from family 4, who had craniometadiaphyseal osteosclerosis with hip dysplasia (CMDOH; 620558), Terhal … (more) In the proband from family 2 and 2 sibs and a cousin from family 4, who had craniometadiaphyseal osteosclerosis with hip dysplasia (CMDOH; 620558), Terhal et al. (2023) identified homozygosity for a c.2167C-T transition (c.2167C-T, NM_003502.3) in exon 7 of the AXIN1 gene, resulting in an arg723-to-ter (R723X) substitution. The consanguineous parents and an unaffected sib in both families were heterozygous for the mutation, which was not found in the gnomAD database. All homozygotes exhibited developmental delay, and 3 had pancytopenia with recurrent infections and 1 had mild anemia. Immunoblot of patient fibroblasts showed a 100-kD band at 20% intensity of the 110-kD band of control fibroblasts; patient mRNA was similarly reduced. In addition, patient fibroblasts showed increased AXIN2 (604025) expression and elevated levels of nonphosphorylated beta-catenin (116806), indicating enhanced canonical Wnt (see 164820) pathway activity in mutant fibroblasts. Overexpression of the R723X variant in HeLa and HEK293T cells demonstrated diffuse cytosolic localization of the mutant, rather than puncta formation as seen with wildtype AXIN1, indicating compromised ability to polymerize. CRISPR/Cas9 introduction of the R723X mutant into HEK293T cells followed by immunoprecipitation analysis showed that protein abundance of the mutant was decreased compared to wildtype AXIN1. A beta-catenin-dependent luciferase assay revealed that the mutant clone displayed basal activation of the Wnt pathway. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.	Terhal P	American journal of human genetics	2023	PMID: 37582359

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_003502.4(AXIN1):c.2167C>T (p.Arg723Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...