2-21006288-C-T

Variant names:

• chr2-21006288-C-T
• rs5742904
• NM_000384.3:c.10580G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM5 PP5_Very_Strong BP4

The NM_000384.3(APOB):​c.10580G>A​(p.Arg3527Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000421 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000322134: Functional studies indicate that the R3527Q variant causes decreased binding of the APOB protein to the LDL receptor (Fisher et al., 1999)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3527W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:67 O:3
• Conservation: PhyloP100: 6.11
• Publications: 190 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322134: Functional studies indicate that the R3527Q variant causes decreased binding of the APOB protein to the LDL receptor (Fisher et al., 1999);; SCV000887561: Published functional studies demonstrate that this variant is damaging to LDL receptor binding (PMIDs: 10388479 (1999), 11115503 (2001)).; SCV002048236: Functional studies show that the variant results in defective LDL binding (Boren 2001). PMID: 11115503.; SCV000426986: Functional studies in transgenic mice showed that the variant resulted in defective LDL receptor binding (PMID: 11115503).; SCV001422754: Animal models in mice demonstrating decreased binding affinity of LDL for its receptor have shown that this variant causes high LDL (PMID: 9486979).; SCV001434274: "functional studies have demonstrated that this variant results in decreased low density lipoprotein (LDL) binding affinity (Benn 2005, Boren 2001)."; SCV001443719: Experimental studies have shown that this missense change disturbs the APOB protein conformation, therefore reducing its ability to act as inhibitor of the LDL receptor (PMID: 11115503, 15797858).; SCV002761491: Functional assays have demonstrated that this missense variant disturbs the APOB protein conformation preventing it from binding LDL, disturbing its normal function as inhibitor of the LDL receptor (PMID: 11115503) (PS3).; SCV004812275: Assessment of the whole LDL receptor cycle in heterologous cells showed defective LDL receptor-binding activity indicating that this variant impacts protein function (PMID: 9486979, 11115503 ).; SCV004822888: Functional studies have shown that the variant affects APOB protein conformation and impairs its binding to the LDLR protein (PMID: 8254047, 9486979, 10388479, 11115503, 15797858).; SCV000902821: Functional studies have shown that the variant affects APOB protein conformation and impairs its binding to the LDLR protein (PMID: 8254047, 9486979, 10388479, 11115503, 15797858).; SCV000541940: Experimental studies have shown that this missense change affects APOB function (PMID: 11115503, 15797858).; SCV003925306: "Functional studies have demonstrated that this variant affects APOB protein conformation and impairs its binding to the LDLR protein [PMID: 8254047, 9486979, 10388479, 11115503, 15797858, 26643808]."; SCV005418341: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV002713792: "In addition, this alteration has been reported to result in defective low-density lipoprotein receptor binding (Boren J et al. J Clin Invest. 1998;101(5):1084-93)."; SCV004046030: Experimental studies have shown that this missense change disturbs the APOB protein conformation, therefore reducing its ability to act as inhibitor of the LDL receptor (PMID: 11115503, 15797858).; SCV004105374: The p.Arg3527Gln substitution has been shown to reduce the binding affinity of LDL receptors to 30% of normal values (Innerarity et al. 1987. PubMed ID: 3477815).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-21006289-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 2-21006288-C-T is Pathogenic according to our data. Variant chr2-21006288-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.044617534). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.10580G>A	p.Arg3527Gln	missense	Exon 26 of 29	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.10580G>A	p.Arg3527Gln	missense	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 250764 AF XY: 0.000303

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1461756 Hom.: 0 Cov.: 36 AF XY: 0.000424 AC XY: 308 AN XY: 727176

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000495 AC: 550 AN: 1111950

Other (OTH) AF: 0.000248 AC: 15 AN: 60392

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152104 Hom.: 1 Cov.: 33 AF XY: 0.000673 AC XY: 50 AN XY: 74290

African (AFR) AF: 0.000121 AC: 5 AN: 41414

American (AMR) AF: 0.000327 AC: 5 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68014

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
23	-	-	Hypercholesterolemia, autosomal dominant, type B (25)
15	-	-	not provided (15)
9	-	-	Hypercholesterolemia, familial, 1 (9)
5	-	-	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (5)
4	-	-	Familial hypercholesterolemia (4)
3	-	-	APOB-related disorder (3)
3	-	-	Familial hypobetalipoproteinemia 1 (3)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	Hypobetalipoproteinemia (1)
1	-	-	See cases (1)
-	-	-	Familial hypercholesterolemia;C4551990:Familial hypobetalipoproteinemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.045	T
MetaSVM	Uncertain	0.46	D
PhyloP100		6.1
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.62
MVP		0.93
MPC		0.26
ClinPred		0.38	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.77
Mutation Taster		=59/41	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: rs5742904; hg19: chr2-21229160;