NM_000384.3(APOB):c.13477CAG[1] (p.Gln4494del) AND Hypercholesterolemia, autosomal dominant, type B

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Oct 21, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000845480.14

Allele description [Variation Report for NM_000384.3(APOB):c.13477CAG[1] (p.Gln4494del)]

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

Gene:

APOB:apolipoprotein B [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

2p24.1

Genomic location:

Preferred name:

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

HGVS:

NC_000002.12:g.21001940CTG[1]
NC_000002.12:g.21001940_21001942delCTG
NG_011793.1:g.47129CAG[1]
NG_042877.1:g.1641_1642insG
NM_000384.3:c.13477CAG[1]MANE SELECT
NP_000375.3:p.Gln4494del
NC_000002.11:g.21224812CTG[1]
NC_000002.11:g.21224812_21224814del
NC_000002.11:g.21224812_21224814delCTG
NM_000384.2:c.13480_13482delCAG
NM_000384.3:c.13480_13482delMANE SELECT
NP_000375.2:p.Q4494del

Protein change:

Q4494del

Links:

dbSNP: rs562574661

NCBI 1000 Genomes Browser:

rs562574661

Molecular consequence:

NM_000384.3:c.13477CAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: Hypercholesterolemia, autosomal dominant, type B (FHCL2)
Synonyms:: APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE; APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE; HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007751; MedGen: C1704417; OMIM: 144010

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000987575	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001440359	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005382112	Institute of Immunology and Genetics Kaiserslautern	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 21, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005398765	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18710658, 24234650, 26643808, 33269076, 33418990, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of mutations in the apolipoprotein B-100 gene and in the PCSK9 gene as the cause of hypocholesterolemia.

Leren TP, Berge KE.

Clin Chim Acta. 2008 Nov;397(1-2):92-5. doi: 10.1016/j.cca.2008.07.025. Epub 2008 Jul 27.

PubMed [citation]

PMID:: 18710658

Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia.

Alves AC, Etxebarria A, Soutar AK, Martin C, Bourbon M.

Hum Mol Genet. 2014 Apr 1;23(7):1817-28. doi: 10.1093/hmg/ddt573. Epub 2013 Nov 13.

PubMed [citation]

PMID:: 24234650

See all PubMed Citations (6)

Details of each submission

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Immunology and Genetics Kaiserslautern, SCV005382112.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG Criteria: PP5, PM4, PS3; Variant was found in heterozygous state

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398765.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia, 2 (MIM#144010) and hypobetalipoproteinaemia (MIM#615558). (I) 0108 - This gene is associated with both recessive and dominant disease. Familial hypercholesterolaemia 2 (MIM#144010) is inherited in an autosomal dominant manner, whereas hypobetalipoproteinaemia (MIM#615558) is recessive (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (104 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated ApoB100_C domain (DECIPHER). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once as likely benign, but moreso as likely pathogenic, pathogenic or as a VUS (ClinVar, LOVD). It has been observed in at least four unrelated heterozygous individuals with familial hypercholesterolaemia, where two had additional pathogenic variants in the PCSK9 gene or the APOB gene. In one family, the variant only partially segregated with disease (PMID: 33269076, PMID: 26643808, PMID: 24234650, PMID: 33418990, PMID: 18710658). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Analysis of patient-derived protein and transfected cells demonstrated reduced LDLR binding capacity, LDL uptake and U937 cell proliferation (PMID: 26643808, PMID: 24234650). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 11, 2025

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