VCV003377072.1 - ClinVar

NM_001348800.3(ZBTB20):c.1897G>A (p.Ala633Thr)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001348800.3(ZBTB20):c.1897G>A (p.Ala633Thr)

Variation ID: 3377072 Accession: VCV003377072.1

Type and length

single nucleotide variant, 1 bp

Location

3: 114339334 (GRCh38) [ NCBI UCSC ] 3: 114058181 (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 25, 2024	Nov 24, 2024	Oct 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001348800.3:c.1897G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001335729.1:p.Ala633Thr	missense
NM_001164342.2:c.1897G>A	NP_001157814.1:p.Ala633Thr	missense
NM_001164343.2:c.1678G>A	NP_001157815.1:p.Ala560Thr	missense
NM_001164344.4:c.1678G>A	NP_001157816.1:p.Ala560Thr	missense
NM_001164345.4:c.1678G>A	NP_001157817.1:p.Ala560Thr	missense
NM_001164346.2:c.1678G>A	NP_001157818.1:p.Ala560Thr	missense
NM_001164347.2:c.1678G>A	NP_001157819.1:p.Ala560Thr	missense
NM_001348801.3:c.1678G>A	NP_001335730.1:p.Ala560Thr	missense
NM_001348802.3:c.1678G>A	NP_001335731.1:p.Ala560Thr	missense
NM_001348803.3:c.1897G>A	NP_001335732.1:p.Ala633Thr	missense
NM_001348804.3:c.1678G>A	NP_001335733.1:p.Ala560Thr	missense
NM_001348805.3:c.1678G>A	NP_001335734.1:p.Ala560Thr	missense
NM_001393393.1:c.1897G>A	NP_001380322.1:p.Ala633Thr	missense
NM_001393394.1:c.1897G>A	NP_001380323.1:p.Ala633Thr	missense
NM_001393395.1:c.1678G>A	NP_001380324.1:p.Ala560Thr	missense
NM_001393396.1:c.1678G>A	NP_001380325.1:p.Ala560Thr	missense
NM_015642.7:c.1678G>A	NP_056457.3:p.Ala560Thr	missense
NR_121662.3:n.562G>A		non-coding transcript variant
NC_000003.12:g.114339334C>T
NC_000003.11:g.114058181C>T
NG_052992.1:g.812947G>A

... more HGVS ... less HGVS

Protein change

A560T, A633T

Other names

Canonical SPDI

NC_000003.12:114339333:C: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

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.
ZBTB20		-	-	GRCh38 GRCh37	282	366

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.
Primrose syndrome	Likely pathogenic (1)	criteria provided, single submitter	Oct 10, 2024	RCV004789663.1

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.
Likely pathogenic (Oct 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primrose syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399754.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 25017102‚ 29737001‚ 32266967 Comment: Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease and loss of function is a likely mechanism of disease in this gene and are associated with Primrose syndrome (MIM#259050). Missense variants are associated with a dominant negative mechanism (PMIDs: 25017102, 29737001). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ala633Val) has been reported once in an individual with Primrose syndrome (PMID: 32266967). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease and loss of function is a likely mechanism of disease in this gene and are associated with Primrose syndrome (MIM#259050). Missense variants are associated with a dominant negative mechanism (PMIDs: 25017102, 29737001). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ala633Val) has been reported once in an individual with Primrose syndrome (PMID: 32266967). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Primrose syndrome: Characterization of the phenotype in 42 patients.	Melis D	Clinical genetics	2020	PMID: 32266967
Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome.	Stellacci E	Human mutation	2018	PMID: 29737001
Mutations in ZBTB20 cause Primrose syndrome.	Cordeddu V	Nature genetics	2014	PMID: 25017102

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001348800.3(ZBTB20):c.1897G>A (p.Ala633Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...