VCV000128421.41 - ClinVar

NM_000384.3(APOB):c.2188G>A (p.Val730Ile)

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(1); Benign(10); Likely benign(2)

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.2188G>A (p.Val730Ile)

Variation ID: 128421 Accession: VCV000128421.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21026844 (GRCh38) [ NCBI UCSC ] 2: 21249716 (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	Oct 5, 2015	Jul 15, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.2188G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Val730Ile	missense
NC_000002.12:g.21026844C>T
NC_000002.11:g.21249716C>T
NG_011793.1:g.22230G>A

Protein change

V730I

Other names

Canonical SPDI

NC_000002.12:21026843: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.

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

Links

ClinGen: CA022806 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	3770	3981

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	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 9, 2017	RCV000116385.28
Hypercholesterolemia, familial, 1	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Mar 1, 2016	RCV000202719.19
Familial hypobetalipoproteinemia 1	Likely benign (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578002.9
Familial hypercholesterolemia	Benign (4)	criteria provided, multiple submitters, no conflicts	May 4, 2023	RCV000771065.14
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 15, 2023	RCV000759455.23
Hypercholesterolemia, autosomal dominant, type B	Likely benign (1)	criteria provided, single submitter	Jan 19, 2018	RCV001094740.12
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001837456.15
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jan 12, 2016	RCV002426658.9

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 (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: SCV000679804.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (2) PubMed: 22095935‚ 25741868 Number of individuals with the variant: 1
Benign (Mar 09, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000729919.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jun 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemias Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000902577.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Jan 19, 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: SCV000427142.3 First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Nov 15, 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: SCV002048356.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024
Benign (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005074071.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Benign (Jun 25, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257677.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303935.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322836.1 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015	Observation 1: Comment on evidence: %MAF (ExAC):2.504 Observation 2:
Benign (Aug 11, 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: SCV000888782.4 First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024	Publications: PubMed (5) PubMed: 22095935‚ 19602640‚ 24503134‚ 33111339‚ 27153395
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: SCV000554836.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: no Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812788.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: European Non-Finnish population allele frequency is 3.501%% (rs12691202, 4518/129062 alleles, 74 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more) European Non-Finnish population allele frequency is 3.501%% (rs12691202, 4518/129062 alleles, 74 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Benign (Jan 12, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002728559.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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 (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918921.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962827.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Feb 09, 2023)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003836795.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Uncertain significance (Aug 22, 2014)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000150309.3 First in ClinVar: May 17, 2014 Last updated: Oct 05, 2015
Uncertain significance (Mar 01, 2016)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588421.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):2.504
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

European Non-Finnish population allele frequency is 3.501%% (rs12691202, 4518/129062 alleles, 74 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1

Comment:

This alteration is classified as 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
Development of a new expanded next-generation sequencing panel for genetic diseases involved in dyslipidemia.	Marmontel O	Clinical genetics	2020	PMID: 33111339
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.	Johansen CT	Journal of lipid research	2014	PMID: 24503134
Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.	Huijgen R	Human mutation	2012	PMID: 22095935
The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine.	Biesecker LG	Genome research	2009	PMID: 19602640

Text-mined citations for this variant ...

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.2188G>A (p.Val730Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...