VCV000237744.59 - ClinVar

NM_000384.3(APOB):c.3427C>T (p.Pro1143Ser)

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.

(16)

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(1); Likely benign(7)

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.3427C>T (p.Pro1143Ser)

Variation ID: 237744 Accession: VCV000237744.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21015451 (GRCh38) [ NCBI UCSC ] 2: 21238323 (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	Apr 9, 2017	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.3427C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Pro1143Ser	missense
NC_000002.12:g.21015451G>A
NC_000002.11:g.21238323G>A
NG_011793.1:g.33623C>T

Protein change

P1143S

Other names

Canonical SPDI

NC_000002.12:21015450: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: CA058842 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	Uncertain significance (2)	criteria provided, single submitter	Mar 28, 2016	RCV000456004.14
Hypercholesterolemia, familial, 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 2, 2018	RCV000497223.12
Familial hypercholesterolemia	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Aug 24, 2022	RCV000771109.11
not provided	Likely benign (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000845457.38
Hypercholesterolemia, autosomal dominant, type B	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001137957.12
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Likely benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001837776.15
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Nov 17, 2021	RCV002450671.9
APOB-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 5, 2024	RCV004529389.2
See cases	Uncertain significance (1)	criteria provided, single submitter	May 10, 2022	RCV004584375.1

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.
Uncertain significance (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: SCV000538327.1 First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017	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: 1 paper, no segs, ExAC: 0.2% European chromosomes (less) Method: Genome/Exome Filtration
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: SCV000588428.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):0.1376
Uncertain significance (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: SCV000782842.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Likely benign (May 09, 2018)	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: SCV000902802.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019	Comment: Likely Benign based on current evidence: This variant (also known as p.Pro1116Ser in the mature protein) is a missense variant located in the beta 1 … (more) Likely Benign based on current evidence: This variant (also known as p.Pro1116Ser in the mature protein) is a missense variant located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Norwegian individual with hypercholesterolemia (PMID: 18710658) but it has also been identified in 464/277174 chromosomes (0.17%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987546.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Likely benign (Oct 04, 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: SCV001133406.4 First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 18710658‚ 22256951
Likely 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: SCV000284767.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Likely benign (Aug 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: SCV001250292.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: APOB: BP4 Number of individuals with the variant: 6
Uncertain significance (Apr 27, 2017)	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: SCV001297956.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 18710658 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jul 23, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001802165.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: This variant is associated with the following publications: (PMID: 22256951, 18710658)
Likely benign (Nov 17, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002614493.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	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)
Uncertain significance (May 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506426.2 First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: BS2 Number of individuals with the variant: 1 Clinical Features: Transient hyperlipidemia (present) Age: 40-49 years Sex: female Tissue: blood
Benign (Aug 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005074060.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
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: SCV001924063.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975473.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Uncertain significance (Mar 05, 2024)	no assertion criteria provided Method: clinical testing	APOB-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104178.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The APOB c.3427C>T variant is predicted to result in the amino acid substitution p.Pro1143Ser. This variant has been reported in individuals with hypercholesterolemia or high … (more) The APOB c.3427C>T variant is predicted to result in the amino acid substitution p.Pro1143Ser. This variant has been reported in individuals with hypercholesterolemia or high HDL-C level (Leren et al. 2008. PubMed ID: 18710658; Motazacker et al. 2013. PubMed ID: 23685560. Table SIV). However, it has also been reported in individuals with low lipid or triglyceride levels (Neale et al. 2011. PubMed ID: 21408211; Xing et al. 2012. PubMed ID: 22256951). This variant is reported in 0.28% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In Clinvar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/237744/). 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)
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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: 1 paper, no segs, ExAC: 0.2% European chromosomes

Comment:

Likely Benign based on current evidence: This variant (also known as p.Pro1116Ser in the mature protein) is a missense variant located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Norwegian individual with hypercholesterolemia (PMID: 18710658) but it has also been identified in 464/277174 chromosomes (0.17%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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.

Comment:

The APOB c.3427C>T variant is predicted to result in the amino acid substitution p.Pro1143Ser. This variant has been reported in individuals with hypercholesterolemia or high HDL-C level (Leren et al. 2008. PubMed ID: 18710658; Motazacker et al. 2013. PubMed ID: 23685560. Table SIV). However, it has also been reported in individuals with low lipid or triglyceride levels (Neale et al. 2011. PubMed ID: 21408211; Xing et al. 2012. PubMed ID: 22256951). This variant is reported in 0.28% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In Clinvar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/237744/). 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.

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
Blindly using Wald's test can miss rare disease-causal variants in case-control association studies.	Xing G	Annals of human genetics	2012	PMID: 22256951
Identification of mutations in the apolipoprotein B-100 gene and in the PCSK9 gene as the cause of hypocholesterolemia.	Leren TP	Clinica chimica acta; international journal of clinical chemistry	2008	PMID: 18710658

Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.3427C>T (p.Pro1143Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...