chr2-21006288-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000384.3(APOB):​c.10580G>T​(p.Arg3527Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). 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: not found (cov: 33)

Consequence

APOB
NM_000384.3 missense

Scores

9
5
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.11
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 2-21006288-C-A is Pathogenic according to our data. Variant chr2-21006288-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-21006288-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOBNM_000384.3 linkc.10580G>T p.Arg3527Leu missense_variant Exon 26 of 29 ENST00000233242.5 NP_000375.3 P04114Q7Z7Q0Q59HB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOBENST00000233242.5 linkc.10580G>T p.Arg3527Leu missense_variant Exon 26 of 29 1 NM_000384.3 ENSP00000233242.1 P04114

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Pathogenic:1
Feb 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3527 of the APOB protein (p.Arg3527Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 16250003, 33269076; Invitae). This variant is also known as p.Arg3500Leu. ClinVar contains an entry for this variant (Variation ID: 440523). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. This variant disrupts the p.Arg3527 amino acid residue in APOB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7627691, 11238294). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hypercholesterolemia, familial, 1 Pathogenic:1
-
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.46
D
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Vest4
0.83
MutPred
0.86
Loss of MoRF binding (P = 0.0054);
MVP
0.94
MPC
0.29
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.84

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5742904; hg19: chr2-21229160; API