rs146377316

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000384.3(APOB):c.9175C>T(p.Arg3059Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 1 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 0.0430

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]

APOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-21007693-G-A is Pathogenic according to our data. Variant chr2-21007693-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 69508.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=5, Pathogenic=1}. Variant chr2-21007693-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.10987711). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.9175C>T	p.Arg3059Cys	missense_variant	26/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.9175C>T	p.Arg3059Cys	missense_variant	26/29	1	NM_000384.3	ENSP00000233242	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250928

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000276

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies showed some reduction in LDL uptake compared to wildtype receptor; however, it is unclear if this reduction is sufficient to cause disease (Motazacker et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as R3032C; This variant is associated with the following publications: (PMID: 31447099, 22408029, 33269076, 30270084, 29290422, 34456049) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2023	The APOB c.9175C>T (p.Arg3059Cys) variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 29290422 (2018), 33269076 (2021), 34456049 (2022), 36105085 (2022)) and is reported to segregate with the disease in one family (PMID: 22408029 (2012)). In addition, functional studies have shown that this variant results in a significant reduction in low density lipoprotein (LDL) uptake (PMID: 22408029 (2012)). The frequency of this variant in the general population, 0.000008 (2/250928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2019

The p.Arg3059Cys variant in APOB has been reported in 3 individuals with autosomal dominant hypercholesterolemia, and segregated with disease in 8 affected relatives of one family, though 2 other family members had the variant but only had mildly elevated high cholesterol (Motazacker et al. 2012). In vitro functional studies looking at LDL uptake provide some evidence that the p.Arg3059Cys variant may impact APOB function (Motazacker et al. 2012). The variant has been reported by other clinical laboratories in ClinVar (Variation ID 69508) and has also been identified in 2/245754 chromosomes of the general population in gnomAD (http://gnomad.broadinstitute.org; dbSNP rs146377316). Conservation analysis shows a lack of conservation at this amino acid site, though replacement by a cysteine has not been observed across species. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg3059Cys variant is likely pathogenic. (ACMG/AMP codes applied: PP1_Strong, PS3_Moderate). Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews). -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3059 of the APOB protein (p.Arg3059Cys). This variant is present in population databases (rs146377316, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 22408029, 29290422; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 69508). 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 not expected to disrupt APOB protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg3059Cys variant in APOB has been reported in 9 individuals with high LDL, segregated with disease in these 9 affected relatives from 1 family (PMID: 22408029), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.0009% (1/113322) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146377316). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg3059Cys variant is uncertain. ACMG/AMP Criteria applied: PP1, PM2, BP4 (Richards 2015). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2024

The p.R3059C variant (also known as c.9175C>T), located in coding exon 26 of the APOB gene, results from a C to T substitution at nucleotide position 9175. The arginine at codon 3059 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was reported in a family with hypercholesterolemia and appeared to segregate with disease in multiple individuals; however, two carrier and two non-carrier family members were identified with similar mildly elevated LDL-C levels. The same study detected this variant in two additional unrelated individuals with elevated LDL-C, but clinical details were limited. In vitro functional analyses indicated some reduction in LDL-uptake with this variant compared to wild-type (Motazacker MM et al. Eur. Heart J., 2012 Jun;33:1360-6). Additionally, this alteration has been reported in familial hypercholesterolemia cohorts (Canepa M et al. Int. J. Cardiol., 2018 Mar;255:215-220; Miroshnikova VV et al. Biomed Rep, 2021 Jan;14:15). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.15

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.51

REVEL

Benign

0.21

Sift

Uncertain

0.020

Sift4G

Uncertain

0.0080

Vest4

0.31

MutPred

0.54

Loss of sheet (P = 0.0357);

MVP

0.47

MPC

0.054

ClinPred

0.048

GERP RS

0.66

gMVP

0.40

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over