rs749903604

Variant names:

• chr2-21042450-G-A
• rs749903604
• NM_000384.3:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21042450-G-A
• chr2-21042450-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000384.3(APOB):​c.148C>T​(p.Arg50Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.953
• Publications: 10 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, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-21042449-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 684875.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 2-21042450-G-A is Pathogenic according to our data. Variant chr2-21042450-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438309.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.148C>T	p.Arg50Trp	missense	Exon 3 of 29	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.148C>T	p.Arg50Trp	missense	Exon 3 of 29	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.148C>T	p.Arg50Trp	missense	Exon 3 of 17	ENSP00000382200.4
	APOB	ENST00000673739.2		n.148C>T		non_coding_transcript_exon	Exon 3 of 25	ENSP00000501110.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251494 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000725 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 04, 2023

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 tryptophan, which is neutral and slightly polar, at codon 50 of the APOB protein (p.Arg50Trp). This variant is present in population databases (rs749903604, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 24498611; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438309). 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%. Studies have shown that this missense change alters APOB peptide levels (PMID: 24498611). This variant disrupts the p.Arg50 amino acid residue in APOB. Other variant(s) that disrupt this residue have been observed in individuals with APOB-related conditions (PMID: 29386597), which suggests that this may be a clinically significant amino acid residue. 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 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

Cardiovascular phenotype Uncertain:1

Sep 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R50W variant (also known as c.148C>T), located in coding exon 3 of the APOB gene, results from a C to T substitution at nucleotide position 148. The arginine at codon 50 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in individuals familial hypercholesterolemia (FH), including segregating wth disease in one family (Thomas ER et al. Mol Genet Genomic Med, 2013 Sep;1:155-61; Futema M et al. J Med Genet, 2014 Aug;51:537-44). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.56	T
PhyloP100		0.95
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.71
MutPred		0.58		Loss of disorder (P = 0.0307)
MVP		0.75
MPC		0.27
ClinPred		0.99	D
GERP RS		1.9
gMVP		0.82
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749903604; hg19: chr2-21265322; COSMIC: COSV51944103;