2-21006289-G-A

Variant names:

• chr2-21006289-G-A
• rs144467873
• NM_000384.3:c.10579C>T
• APOB p.Arg3527Trp

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP3_ModeratePP5_Strong

The NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000576 (AC=93) in the gnomAD database across 1,613,988 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00038. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000914259: Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. PMID:10496864" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R3527L: Likely_pathogenic (ClinVar VariationId 440523, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R3527= (synonymous): Likely_benign (ClinVar VariationId 2773803, 2 stars); p.R3527= (synonymous): Likely_benign (ClinVar VariationId 928679, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 U:1 O:1
• Conservation: PhyloP100: 4.09
• Publications: 63 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000914259: Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. PMID:10496864; SCV001422753: Animal models in mice have shown that this variant causes hypercholesteremia (PMID: 9486979).; SCV001573163: Experiments using patient derived skin fibroblast cells that contain the p.Arg3527Trw variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. In addition, the proliferation rate of U937 cells containing the p.Arg3527Trp substitution supplied with LDL was fourfold less than wild type controls.; SCV004822899: Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294).; SCV005417848: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000583115: Published functional studies demonstrate that the variant reduced APOB capacity for binding, uptake, and degradation of LDL (Fisher et al., 1999);; SCV002046141: Assessment of experimental evidence regarding the effect of this variant suggests it is detrimental to normal function (PMID: 11238294 (2001), 10388479 (1999), and 7627691 (1995)).; SCV001347007: Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294).; SCV000712357: "In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294)."; SCV003925320: Functional studies suggest this variant reduces binding, uptake, and degradation of LDL [PMID:7627691,11238294].; SCV002712483: "In addition, in vitro studies have reported this alteration to attenuate protein function (Gaffney D et al. Arterioscler Thromb Vasc Biol. 1995;15:1025-9; Gaffney D et al. Arterioscler Thromb Vasc Biol. 1995;15:1025-9; Tai ES et al. Clin Chem. 2001;47:438-43)."
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00038 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000421 by highest known P/LP ClinVar AF 0.000421) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R3527L: Likely_pathogenic (ClinVar VariationId 440523, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R3527= (synonymous): Likely_benign (ClinVar VariationId 2773803, 2 stars); p.R3527= (synonymous): Likely_benign (ClinVar VariationId 928679, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (33/34 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APOB NM_000384.3	MANE Select	c.10579C>T p.Arg3527Trp	missense	Exon 26 of 29	Prot: NP_000375.3 UniProt:

APOB NM_000384.3

MANE Select

HGVSc / HGVSpc.10579C>Tp.Arg3527Trp

Exon rankExon 26 of 29

missense

Prot: NP_000375.3UniProt: P04114Q7Z7Q0Q59HB3A0AAG2UUW0

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APOB ENST00000233242.5	TSL:1MANE Select	c.10579C>T p.Arg3527Trp	missense	Exon 26 of 29	Prot: ENSP00000233242.1 UniProt:

APOB ENST00000233242.5

TSL:1MANE Select

HGVSc / HGVSpc.10579C>Tp.Arg3527Trp

Exon rankExon 26 of 29

missense

Prot: ENSP00000233242.1UniProt: P04114

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000854	AC:13	Hom:0	AN:152142	Cov:33
GnomAD2 exomes	AF: 0.000172	AC:43	Hom:	AN:250718	Cov:
GnomAD4 exome	AF: 0.0000547	AC:80	Hom:0	AN:1461728	Cov:36
GnomAD4 genome	AF: 0.0000854	AC:13	Hom:0	AN:152260	Cov:33
TOPMed (Bravo)	AF: 0.0000718	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000764	AC:14	Hom:0	AN:183128	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.00128	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.000577	AC:2	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122754	Cov:
Turkish Variome	AF: 0.000298	AC:2	Hom:0	AN:6720	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00112	AC:10	Hom:0	AN:8960	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000715	3	41958	0.000105	7	66888
SCHEMA(Schizophrenia)	0.000308	33	107312	0.000132	24	181986

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Hypercholesterolemia, autosomal dominant, type B (12)
7	-	-	not provided (7)
3	1	-	Hypercholesterolemia, familial, 1 (4)
3	-	-	APOB-related disorder (3)
3	-	-	Familial hypercholesterolemia (3)
3	-	-	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypobetalipoproteinemia 1 (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.45	D
Mutation Taster	N/A	20/80	disease causing (ClinVar)
PhyloP100	Uncertain	4.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
VESM-3B	Benign	-8.9

Showing 24 of 24 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs144467873;

hg19: chr2-21229161;

COSMIC: COSV51924033;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar