chr2-21006686-C-A

Variant names:

• chr2-21006686-C-A
• rs1382988295
• NM_000384.3:c.10182G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PM5 PP5_Very_Strong

The NM_000384.3(APOB):​c.10182G>T​(p.Lys3394Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3394T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.628
• Publications: 3 publications found

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]

APOB Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_000384.3 (APOB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000384.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-21006687-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1046270.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 2-21006686-C-A is Pathogenic according to our data. Variant chr2-21006686-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.10182G>T	p.Lys3394Asn	missense_variant	Exon 26 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.10182G>T	p.Lys3394Asn	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461762 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Pathogenic:2

Jan 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOB protein function. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 22408029). ClinVar contains an entry for this variant (Variation ID: 438310). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 3394 of the APOB protein (p.Lys3394Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Pathogenic:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APOB c.10182G>T; p.Lys3394Asn variant (rs1382988295, ClinVar Variation ID: 438310), is reported in the literature in multiple individuals affected with familial hypercholesterolemia (Motazacker 2012, Reijman 2023, Sturm 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.281). In vitro functional analyses found this variant attenuated binding to the LDLR significantly (Motazacker 2012). Based on available information, this variant is considered to be likely pathogenic. References: Motazacker MM et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur Heart J. 2012 Jun;33(11):1360-6. PMID: 22408029. Reijman MD et al. Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia. Curr Opin Lipidol. 2023 Dec 1;34(6):287-295. PMID: 36752612. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.49	T
PhyloP100		0.63
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.53
MutPred		0.46		Loss of sheet (P = 0.0457);
MVP		0.67
MPC		0.29
ClinPred		1.0	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.69
Mutation Taster		=49/51	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1382988295; hg19: chr2-21229558;