chr2-21006289-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM5 PP5_Very_Strong

The NM_000384.3(APOB):​c.10579C>T​(p.Arg3527Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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; 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)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3527Q) has been classified as Likely pathogenic.

• 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:31 U:1 O:1
• Conservation: PhyloP100: 4.09
• Publications: 55 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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)."
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant 2-21006289-G-A is Pathogenic according to our data. 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.

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.10579C>T	p.Arg3527Trp	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.10579C>T	p.Arg3527Trp	missense	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000172 AC: 43 AN: 250718 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461728 Hom.: 0 Cov.: 36 AF XY: 0.0000646 AC XY: 47 AN XY: 727168

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: 26134

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000784 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Hypercholesterolemia, autosomal dominant, type B (11)
7	-	-	not provided (7)
3	1	-	Hypercholesterolemia, familial, 1 (4)
3	-	-	Familial hypercholesterolemia (3)
3	-	-	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (3)
2	-	-	APOB-related disorder (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypobetalipoproteinemia 1 (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.45	D
PhyloP100		4.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.80
MVP		0.93
MPC		0.28
ClinPred		0.48	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.84
Mutation Taster		=20/80	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: rs144467873; hg19: chr2-21229161; COSMIC: COSV51924033;