VCV001120264.2 - ClinVar

NM_032607.3(CREB3L3):c.138G>A (p.Trp46Ter)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032607.3(CREB3L3):c.138G>A (p.Trp46Ter)

Variation ID: 1120264 Accession: VCV001120264.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 4155009 (GRCh38) [ NCBI UCSC ] 19: 4155006 (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	Jun 8, 2021	Feb 14, 2024	Sep 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_032607.3:c.138G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115996.1:p.Trp46Ter	nonsense
NM_001271995.2:c.138G>A	NP_001258924.1:p.Trp46Ter	nonsense
NM_001271996.2:c.138G>A	NP_001258925.1:p.Trp46Ter	nonsense
NM_001271997.2:c.138G>A	NP_001258926.1:p.Trp46Ter	nonsense
NC_000019.10:g.4155009G>A
NC_000019.9:g.4155006G>A

... more HGVS ... less HGVS

Protein change

Other names

W46*

Canonical SPDI

NC_000019.10:4155008: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: 611998.0002 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.
CREB3L3		-	-	GRCh38 GRCh37	180	244

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.
Hypertriglyceridemia 2	risk factor (1)	no assertion criteria provided	May 17, 2021	RCV001450096.1
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 13, 2023	RCV003558831.2

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 (Sep 13, 2023)	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: SCV004297980.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 21666694‚ 26427795‚ 32041611 Comment: This sequence change creates a premature translational stop signal (p.Trp46) in the CREB3L3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp46) in the CREB3L3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CREB3L3 are known to be pathogenic (PMID: 21666694, 26427795). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with CREB3L3-related conditions (PMID: 21666694, 32041611). ClinVar contains an entry for this variant (Variation ID: 1120264). For these reasons, this variant has been classified as Pathogenic. (less)
risk factor (May 17, 2021)	no assertion criteria provided Method: literature only	HYPERTRIGLYCERIDEMIA, SUSCEPTIBILITY TO, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001653685.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Publications: PubMed (1) PubMed: 21666694 Comment on evidence: In a male proband (GL1329) with hypertriglyceridemia (HYTG2; 619324), Lee et al. (2011) identified heterozygosity for a mutation in the CREB3L3 gene resulting in a … (more) In a male proband (GL1329) with hypertriglyceridemia (HYTG2; 619324), Lee et al. (2011) identified heterozygosity for a mutation in the CREB3L3 gene resulting in a trp46-to-ter (W46X) substitution, which was predicted to preclude translation of the DNA-binding and bZIP domains. In transactivation assays, the W46X mutant failed to activate any of the reporters. Although the proband's carrier father had a triglyceride level in the normal range, aggregate lipoprotein profiles of the nuclear families of 4 probands with CREB3L3 nonsense mutations, including W46X, showed significantly elevated mean plasma triglyceride levels in the 11 mutation carriers compared with 5 noncarrier first-degree relatives (p = 0.021). (less)

Comment:

This sequence change creates a premature translational stop signal (p.Trp46*) in the CREB3L3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CREB3L3 are known to be pathogenic (PMID: 21666694, 26427795). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with CREB3L3-related conditions (PMID: 21666694, 32041611). ClinVar contains an entry for this variant (Variation ID: 1120264). For these reasons, this variant has been classified as Pathogenic.

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
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
Novel CREB3L3 Nonsense Mutation in a Family With Dominant Hypertriglyceridemia.	Cefalù AB	Arteriosclerosis, thrombosis, and vascular biology	2015	PMID: 26427795
The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism.	Lee JH	Nature medicine	2011	PMID: 21666694

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_032607.3(CREB3L3):c.138G>A (p.Trp46Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...