VCV000265896.26 - ClinVar

NM_000384.3(APOB):c.13477CAG[1] (p.Gln4494del)

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.

(11)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(5); Uncertain significance(4); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000384.3(APOB):c.13477CAG[1] (p.Gln4494del)

Variation ID: 265896 Accession: VCV000265896.26

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 2p24.1 2: 21001940-21001942 (GRCh38) [ NCBI UCSC ] 2: 21224812-21224814 (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	Oct 15, 2016	Oct 26, 2024	Oct 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.13477CAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Gln4494del	inframe deletion
NM_000384.3:c.13480_13482del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.21001940CTG[1]
NC_000002.11:g.21224812CTG[1]
NG_011793.1:g.47129CAG[1]
NG_042877.1:g.1641_1642insG

... more HGVS ... less HGVS

Protein change

Q4494del

Other names

Canonical SPDI

NC_000002.12:21001939:CTGCTG:CTG

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: CA1546518 dbSNP: rs562574661 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.
APOB		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3547	3750

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.
Hypercholesterolemia, familial, 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 1, 2016	RCV000256307.15
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 3, 2023	RCV001283874.11
Hypercholesterolemia, autosomal dominant, type B	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 21, 2024	RCV000845480.12
not specified	Uncertain significance (1)	criteria provided, single submitter	May 4, 2022	RCV002248497.9
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Oct 27, 2022	RCV002379100.9
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Likely benign (1)	criteria provided, single submitter	Jan 18, 2024	RCV001837820.15

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 (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322867.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Publications: PubMed (1) PubMed: 24234650 Comment: 0/192 non-FH alleles Observation 1: Comment on evidence: %MAF (ExAC):0.05123 Observation 2: Comment on evidence: Heterozygous patient LDL, U937 cells proliferation; lymphocytes and HepG2 cells, FACS assays Result: 40% proliferation; 50-60% binding and internalization
Uncertain significance (-)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484835.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Number of individuals with the variant: 1
Likely pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588469.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Publications: PubMed (1) PubMed: 24234650 Observation 1: Comment on evidence: %MAF(ExAC):0.05123 Observation 2: Comment on evidence: Assay description:Htz patient LDL, U937 cells proliferation; lymphocytes and HepG2 cells, FACS assays Result: 40% proliferation; 50-60% binding and internalization
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987575.1 First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440359.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Uncertain significance (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516909.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Uncertain significance (Nov 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003921569.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: Published functional studies demonstrate a damaging effect through a 40% decrease in internalization in lymphocytes and HepG2 cells (Alves et al., 2014); In silico analysis … (more) Published functional studies demonstrate a damaging effect through a 40% decrease in internalization in lymphocytes and HepG2 cells (Alves et al., 2014); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26643808, 24234650, 32719484, 32770674, 33269076, 33418990, 33303402, 35913489, 31980526) (less)
Uncertain significance (Aug 03, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469332.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (11) PubMed: 32770674‚ 32719484‚ 33269076‚ 33418990‚ 33508743‚ 29386597‚ 31980526‚ 33303402‚ 24234650‚ 26643808‚ 35913489 Comment: In the published literature, this variant has been reported in individuals affected with hypercholesterolemia (PMIDs: 31980526 (2020), 32770674 (2020), 33269076 (2021), 33303402 (2021), 33418990 (2021), … (more) In the published literature, this variant has been reported in individuals affected with hypercholesterolemia (PMIDs: 31980526 (2020), 32770674 (2020), 33269076 (2021), 33303402 (2021), 33418990 (2021), and 35913489 (2022)), and did not fully co-segregate in one family (PMID: 24234650 (2014)). Additionally, functional studies have shown this variant caused impaired LDL binding and uptake (PMIDs: 24234650 (2014) and 26643808 (2015)). The frequency of this variant in the general population, 0.0007 (90/128394 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Likely benign (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659268.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Oct 27, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002690280.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 18266662‚ 18710658‚ 24234650‚ 26643808‚ 31980526‚ 32719484‚ 32770674‚ 33269076‚ 33303402‚ 33418990 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely pathogenic (Oct 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382112.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PP5, PM4, PS3; Variant was found in heterozygous state
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Comment:

Published functional studies demonstrate a damaging effect through a 40% decrease in internalization in lymphocytes and HepG2 cells (Alves et al., 2014); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26643808, 24234650, 32719484, 32770674, 33269076, 33418990, 33303402, 35913489, 31980526)

Comment:

In the published literature, this variant has been reported in individuals affected with hypercholesterolemia (PMIDs: 31980526 (2020), 32770674 (2020), 33269076 (2021), 33303402 (2021), 33418990 (2021), and 35913489 (2022)), and did not fully co-segregate in one family (PMID: 24234650 (2014)). Additionally, functional studies have shown this variant caused impaired LDL binding and uptake (PMIDs: 24234650 (2014) and 26643808 (2015)). The frequency of this variant in the general population, 0.0007 (90/128394 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Universal screening for familial hypercholesterolemia in 2 populations.	Sustar U	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 35913489
Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.	Futema M	Atherosclerosis	2021	PMID: 33508743
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.	Meshkov A	Genes	2021	PMID: 33418990
Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.	Gill PK	Journal of clinical lipidology	2021	PMID: 33303402
Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing.	Miroshnikova VV	Biomedical reports	2021	PMID: 33269076
Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.	Rieck L	Clinical genetics	2020	PMID: 32770674
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia.	Elbitar S	Scientific reports	2018	PMID: 29386597
Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity.	Fernández-Higuero JA	Scientific reports	2015	PMID: 26643808
Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia.	Alves AC	Human molecular genetics	2014	PMID: 24234650
Identification of mutations in the apolipoprotein B-100 gene and in the PCSK9 gene as the cause of hypocholesterolemia.	Leren TP	Clinica chimica acta; international journal of clinical chemistry	2008	PMID: 18710658
Characterization of novel mutations in the catalytic domain of the PCSK9 gene.	Cameron J	Journal of internal medicine	2008	PMID: 18266662
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Text-mined citations for rs562574661 ...

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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.13477CAG[1] (p.Gln4494del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs562574661 ...