rs562574661

Variant names:

• chr2-21001939-ACTG-A
• rs562574661
• NM_000384.3:c.13480_13482delCAG

Your query was ambiguous. Multiple possible variants found:

• chr2-21001939-ACTG-A
• chr2-21001939-ACTG-ACTGCTG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000384.3(APOB):​c.13480_13482delCAG​(p.Gln4494del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: APOB NM_000384.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:6 B:2
• Conservation: PhyloP100: 3.04

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000384.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.13480_13482delCAG	p.Gln4494del	conservative_inframe_deletion	Exon 29 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.13480_13482delCAG	p.Gln4494del	conservative_inframe_deletion	Exon 29 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000384 AC: 96 AN: 250322 Hom.: 0 AF XY: 0.000391 AC XY: 53 AN XY: 135440

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000735

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000380 AC: 555 AN: 1461758 Hom.: 1 AF XY: 0.000338 AC XY: 246 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000189

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B Pathogenic:3 Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/192 non-FH alleles -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jun 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APOB c.13480_13482del (p.Gln4494del) variant has been reported in the published literature 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. ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 265896). Based on the available information, we are unable to determine the clinical significance of this variant. -

Nov 30, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1 Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln4494del variant in APOB gene has been previously reported in at least 4 unrelated individuals affected with familial hypercholesterolemia (Alves et al., 2014; Rieck et al., 2020; Miroshnikova et al., 2021). This variant did not completely segregate with disease in one family (Alves et al., 2014). This variant has been identified in 90/128,394 European non-Finnish chromosomes (104/281,716 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been observed in the population at a frequency higher than expected for a potentially disease-causing variant. The p.Gln4494del variant results in an in-frame deletion of 1 amino acid in exon 29 of the APOB gene. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. Functional studies of this variant demonstrated a reduction in the binding and uptake of LDL and a change to the secondary structure of the ApoB100 protein (Alves et al., 2014; Fernández-Higuero et al., 2015). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, despite some supporting functional evidence the significance of the p.Gln4494del variant is uncertain due to limited case data and population frequency data. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1; PS3_Moderate; PP3] -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 27, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs562574661; hg19: chr2-21224811;