rs756209187

Positions:

chr2-21006629-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000384.3(APOB):c.10238del(p.Thr3413MetfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000167 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

APOB
NM_000384.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.74

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-21006629-AG-A is Pathogenic according to our data. Variant chr2-21006629-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 434252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21006629-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.10238del	p.Thr3413MetfsTer2	frameshift_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.10238del	p.Thr3413MetfsTer2	frameshift_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251264

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135812

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Thr3413Metfs*2) in the APOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APOB are known to be pathogenic (PMID: 20032471). This variant is present in population databases (rs756209187, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal dominant hypobetalipoproteinemia (PMID: 1431583). This variant is also known as c.10366del. ClinVar contains an entry for this variant (Variation ID: 434252). For these reasons, this variant has been classified as Pathogenic. -

Hypobetalipoproteinemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also referred to as c.10366del in the literature. This frameshifting variant in exon 26 of 29 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with Hypobetalipoproteinemia (PMID: 1431583). Loss-of-function variation in APOB is an established mechanism of disease (PMID: 30939045). Experimental studies have shown that this c.10238del (p.Thr3413MetfsTer2) change results in decreased LDL-cholesterol levels and reduced APOB protein concentrations (PMID: 1431583). The c.10238del (p.Thr3413MetfsTer2) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (2/282662) and thus is presumed to be rare. Based on the available evidence, the c.10238del (p.Thr3413MetfsTer2) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2016	- -

Hypercholesterolemia, autosomal dominant, type B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 14, 2022

The heterozygous c.10238del variant in APOB has previously been reported in individuals with associated familial hypercholesterolemia [PMID: 32719484] and it has been deposited in ClinVar (Var ID: 434252) as Pathogenic/Likely pathogenic. The c.10238del variant is observed in 7 alleles (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.10238del variant in APOB is located in exon 26 of this 29-exon gene, predicted to incorporate a premature termination codon (p.(Thr3413MetfsTer2)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.10238del variant have been reported in ClinVar or literature in affected individuals. Based on available evidence this inherited c.10238del, p.(Thr3413MetfsTer2) variant identified in APOB is classified as Likely Pathogenic. -

APOB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The APOB c.10238delC variant is predicted to result in a frameshift and premature protein termination (p.Thr3413Metfs*2). This variant has been reported to segregate with disease in a three-generation family with hypobetalipoproteinemia (Krul et al. 1992. PubMed ID: 1431583). It has also been reported in individuals with nonalcoholic fatty liver disease (Vilar-Gomez et al. 2021. PubMed ID: 33454241). This variant is reported in 0.0016% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in APOB are expected to be pathogenic and this variant has been interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/434252/). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 21, 2022

- -

Familial hypobetalipoproteinemia 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 22, 2020

The p.Thr3413Metfs variant in APOB has not been previously reported in individuals with low LDL but has been identified in in 0.00155% (2/129014) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756209187). This variant has also been reported in ClinVar (VariationID: 434252) as pathogenic by the University of Chicago. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 3413 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the APOB gene is an established disease mechanism in autosomal recessive low LDL. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.10238delC pathogenic mutation, located in coding exon 26 of the APOB gene, results from a deletion of one nucleotide at nucleotide position 10238, causing a translational frameshift with a predicted alternate stop codon (p.T3413Mfs*2). This variant has been detected in the heterozygous state in individuals with low LDL cholesterol, some of whom also had fatty liver disease (Krul ES et al. J Lipid Res. 1992 Jul;33(7):1037-50; Vilar-Gomez E et al. J Clin Lipidol. 2021 Dec;15(2):275-291). One study reported this variant to result in increased LDL receptor binding (Krul ES et al. J Lipid Res. 1992 Jul;33(7):1037-50). Although biallelic loss of function alterations in APOB have been associated with autosomal recessive hypobetalipoproteinemia, haploinsufficiency for APOB has not been clearly established as a mechanism of disease for autosomal dominant familial hypercholesterolemia. Based on the supporting evidence, this variant would be expected to cause autosomal recessive hypobetalipoproteinemia when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant familial hypercholesterolemia is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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