VCV000281142.62 - ClinVar

NM_000384.3(APOB):c.3383G>A (p.Arg1128His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(4); Likely benign(9)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000384.3(APOB):c.3383G>A (p.Arg1128His)

Variation ID: 281142 Accession: VCV000281142.62

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21015495 (GRCh38) [ NCBI UCSC ] 2: 21238367 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.3383G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Arg1128His	missense
NC_000002.12:g.21015495C>T
NC_000002.11:g.21238367C>T
NG_011793.1:g.33579G>A

Protein change

R1128H

Other names

Canonical SPDI

NC_000002.12:21015494:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00280 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00280

1000 Genomes Project 30x 0.00281

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00323

The Genome Aggregation Database (gnomAD) 0.00356

Trans-Omics for Precision Medicine (TOPMed) 0.00364

Exome Aggregation Consortium (ExAC) 0.00371

The Genome Aggregation Database (gnomAD), exomes 0.00378

Links

ClinGen: CA058710 dbSNP: rs12713843 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APOB		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3550	3753

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Likely benign (1)	criteria provided, single submitter	Mar 28, 2016	RCV000295629.15
Hypercholesterolemia, autosomal dominant, type B	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 22, 2020	RCV000578081.18
Hypercholesterolemia, familial, 1	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Aug 22, 2023	RCV000583315.14
Primary familial dilated cardiomyopathy	Likely benign (1)	criteria provided, single submitter	-	RCV000845396.11
Familial hypobetalipoproteinemia 1	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000577967.9
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000723752.43
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001837821.14
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Oct 18, 2018	RCV002450797.9
APOB-related disorder	Uncertain significance (1)	criteria provided, single submitter	Feb 13, 2023	RCV004529460.1
Familial hypercholesterolemia	Benign (1)	criteria provided, single submitter	Sep 26, 2022	RCV004584654.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538318.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (116/16506) South Asian chromosomes (less) Method: Genome/Exome Filtration
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679805.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypobetalipoproteinemia 1 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679806.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Number of individuals with the variant: 1
Likely benign (Jan 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000782840.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Uncertain significance (Aug 27, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331502.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APOB Number of individuals with the variant: 4 Sex: mixed
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial dilated cardiomyopathy Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987460.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Uncertain significance (May 18, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001297957.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jun 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730570.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 14732481, 28008009, 26332594, 21408211, 27153395, 20981092, 30782561, 31150472, 26582918)
Likely benign (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hypercholesterolemia, autosomal dominant, type B (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422586.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ecf90307-b784-42a1-ae0b-d1ceb8a5630e Comment: The p.Arg1128His variant in APOB has been reported in 2 Caucasian individuals suspected to have familial hypercholesterolemia (DOI: 10.1016/S0735-1097(18)32309-X), and has been identified in 0.7219% … (more) The p.Arg1128His variant in APOB has been reported in 2 Caucasian individuals suspected to have familial hypercholesterolemia (DOI: 10.1016/S0735-1097(18)32309-X), and has been identified in 0.7219% (221/30614) of South Asian chromosomes, including 6 homozygotes, 0.4949% (639/129122) of European (non-Finnish) chromosomes, including 3 homozygotes, and 0.3753% (133/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12713843). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 281142). 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, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015). (less)
Likely benign (Jun 26, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000687231.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001135625.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Uncertain significance (Feb 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	APOB-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004103508.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The APOB c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. This variant has been reported as a variant of uncertain significance … (more) The APOB c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. This variant has been reported as a variant of uncertain significance in an individual with primary hypocholesterolemia (Blanco-Vaca et al. 2019. PubMed ID: 30782561). In addition, this variant has been identified in three individuals with low lipid levels (Neale et al. 2011. PubMed ID: 21408211). This variant is reported in 0.72% of alleles in individuals of South Asian descent, and in nine homozygotes in gnomAD (http://gnomad.broadinstitute.org/variant/2-21238367-C-T), which suggests that it may be too common to be a primary cause of disease. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to likely benign, to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/281142/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Benign (Jun 30, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001133405.4 First in ClinVar: Jan 04, 2020 Last updated: Jan 06, 2024	Publications: PubMed (8) PubMed: 30782561‚ 31150472‚ 14732481‚ 26332594‚ 28008009‚ 27153395‚ 21408211‚ 30270084
Likely benign (Oct 23, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004562152.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659280.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Likely benign (Oct 18, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002618278.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 20981092‚ 26332594‚ 27153395‚ 28008009‚ 30270084 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Sep 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005074063.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001152158.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: APOB: BP4 Number of individuals with the variant: 34
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (116/16506) South Asian chromosomes

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The p.Arg1128His variant in APOB has been reported in 2 Caucasian individuals suspected to have familial hypercholesterolemia (DOI: 10.1016/S0735-1097(18)32309-X), and has been identified in 0.7219% (221/30614) of South Asian chromosomes, including 6 homozygotes, 0.4949% (639/129122) of European (non-Finnish) chromosomes, including 3 homozygotes, and 0.3753% (133/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12713843). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 281142). 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, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).

Comment:

The APOB c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. This variant has been reported as a variant of uncertain significance in an individual with primary hypocholesterolemia (Blanco-Vaca et al. 2019. PubMed ID: 30782561). In addition, this variant has been identified in three individuals with low lipid levels (Neale et al. 2011. PubMed ID: 21408211). This variant is reported in 0.72% of alleles in individuals of South Asian descent, and in nine homozygotes in gnomAD (http://gnomad.broadinstitute.org/variant/2-21238367-C-T), which suggests that it may be too common to be a primary cause of disease. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to likely benign, to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/281142/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels.	Khlebus E	PloS one	2019	PMID: 31150472
Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: Evidence supporting polygenicity in mutation-negative patients.	Blanco-Vaca F	Atherosclerosis	2019	PMID: 30782561
Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia.	Alves AC	Atherosclerosis	2018	PMID: 30270084
Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.	Dewey FE	Science (New York, N.Y.)	2016	PMID: 28008009
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
Testing for an unusual distribution of rare variants.	Neale BM	PLoS genetics	2011	PMID: 21408211
A map of human genome variation from population-scale sequencing.	1000 Genomes Project Consortium	Nature	2010	PMID: 20981092
Hypobetalipoproteinemia with an apparently recessive inheritance due to a "de novo" mutation of apolipoprotein B.	Lancellotti S	Biochimica et biophysica acta	2004	PMID: 14732481
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APOB	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ecf90307-b784-42a1-ae0b-d1ceb8a5630e	-	-	-	-
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Text-mined citations for rs12713843 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.3383G>A (p.Arg1128His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs12713843 ...