VCV000255979.29 - ClinVar

NM_000384.3(APOB):c.1594C>T (p.Arg532Trp)

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.

(13)

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(7); Likely benign(3)

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.1594C>T (p.Arg532Trp)

Variation ID: 255979 Accession: VCV000255979.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21029662 (GRCh38) [ NCBI UCSC ] 2: 21252534 (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 3, 2016	Jun 23, 2024	Jun 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.1594C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Arg532Trp	missense
NC_000002.12:g.21029662G>A
NC_000002.11:g.21252534G>A
NG_011793.1:g.19412C>T

Protein change

R532W

Other names

Canonical SPDI

NC_000002.12:21029661:G:A

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: CA053978 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	3739	3949

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 (2)	criteria provided, single submitter	-	RCV000243074.16
Familial hypobetalipoproteinemia 1	Likely benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000337679.13
Hypercholesterolemia, familial, 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 2, 2018	RCV000407187.17
Warfarin response	drug response (1)	no assertion criteria provided	Aug 31, 2010	RCV000845575.10
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Mar 29, 2023	RCV000985334.14
Hypercholesterolemia, autosomal dominant, type B	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001094705.12
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001837799.15
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Oct 4, 2016	RCV002401954.9
Familial hypercholesterolemia	Benign (1)	criteria provided, single submitter	Jun 19, 2024	RCV004577520.1

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303933.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Benign (Mar 29, 2023)	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: SCV001133395.4 First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024	Publications: PubMed (9) PubMed: 23593297‚ 26690388‚ 26612772‚ 27516387‚ 29083407‚ 29036232‚ 29353225‚ 30420299‚ 30526649
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: SCV000659271.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Benign (Jun 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005061707.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588418.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):1.138
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: SCV000782820.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial hypobetalipoproteinemia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000427152.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 12, 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: SCV000427153.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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: SCV000687212.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Jul 12, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001948663.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 29353225, 23593297, 26690388, 26612772, 29036232, 27516387, 29083407, 30526649, 30420299)
Benign (Oct 04, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002705760.2 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: research	Not specified Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000605979.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
drug response (Aug 31, 2010)	no assertion criteria provided Method: research	Warfarin response Drug used for hemorrhage Affected status: no Allele origin: unknown	Pharmacogenomics Lab, Chungbuk National University Accession: SCV000889940.1 First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019	Number of individuals with the variant: 139
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease.	Cao YX	Journal of translational medicine	2018	PMID: 30526649
Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis.	Jin JL	EBioMedicine	2018	PMID: 30420299
Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.	Pek SLT	Atherosclerosis	2018	PMID: 29353225
Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.	Lu X	Nature genetics	2017	PMID: 29083407
Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels.	Lee CJ	PloS one	2017	PMID: 29036232
Coding-sequence variants are associated with blood lipid levels in 14,473 Chinese.	Lu X	Human molecular genetics	2016	PMID: 27516387
Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B.	Yilmaz BS	Clinica chimica acta; international journal of clinical chemistry	2016	PMID: 26612772
Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese.	Tang CS	Nature communications	2015	PMID: 26690388
Genetic polymorphisms in LDLR, APOB, PCSK9 and other lipid related genes associated with familial hypercholesterolemia in Malaysia.	Lye SH	PloS one	2013	PMID: 23593297

Text-mined citations for this variant ...

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.1594C>T (p.Arg532Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...