VCV000431492.28 - ClinVar

NM_000384.3(APOB):c.2863C>T (p.Pro955Ser)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(6); Benign(2); Likely benign(1)

9 out of 9 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000384.3(APOB):c.2863C>T (p.Pro955Ser)

Variation ID: 431492 Accession: VCV000431492.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21019859 (GRCh38) [ NCBI UCSC ] 2: 21242731 (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	Aug 13, 2017	Mar 11, 2025	Nov 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3:c.2863C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Pro955Ser	missense
NC_000002.12:g.21019859G>A
NC_000002.11:g.21242731G>A
NG_011793.1:g.29215C>T

Protein change

P955S

Other names

Canonical SPDI

NC_000002.12:21019858: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: CA057430 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	4017	4241

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.
Hypercholesterolemia, familial, 1	Uncertain significance (1)	criteria provided, single submitter	Mar 1, 2016	RCV000497045.10
Familial hypobetalipoproteinemia 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001138063.12
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Likely benign (1)	criteria provided, single submitter	Nov 21, 2024	RCV001837930.16
Familial hypercholesterolemia	Benign (1)	criteria provided, single submitter	Jul 19, 2024	RCV004772941.1
Hypercholesterolemia, autosomal dominant, type B	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001138062.12
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 13, 2024	RCV001576522.14
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Aug 9, 2016	RCV002438204.9
APOB-related disorder	Uncertain significance (1)	criteria provided, single submitter	Apr 1, 2023	RCV004527603.1

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 01, 2016) C Contributing to aggregate classification	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: SCV000588423.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):0.02306
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	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: SCV001298085.1 First in ClinVar: May 31, 2020 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	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: SCV001298086.1 First in ClinVar: May 31, 2020 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 11, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001803728.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: Reported as a single nucleotide polymorphism associated with high LDL-C levels in exome wide association studies and has been reported in association with hypertriglyceridemia (Yamada … (more) Reported as a single nucleotide polymorphism associated with high LDL-C levels in exome wide association studies and has been reported in association with hypertriglyceridemia (Yamada et al., 2019; Tada et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30718733, 28473662, 30389453, 33020668, 30365130) (less)
Uncertain significance (Apr 01, 2023) C Contributing to aggregate classification	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: SCV004106400.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The APOB c.2863C>T variant is predicted to result in the amino acid substitution p.Pro955Ser. This variant has been reported in individuals with dyslipidemia, although no … (more) The APOB c.2863C>T variant is predicted to result in the amino acid substitution p.Pro955Ser. This variant has been reported in individuals with dyslipidemia, although no further evidence was provided to determine its pathogenicity (Yamada et al. 2017. PubMed ID: 28473662; Yamada et al. 2019. PubMed ID: 30365130. Table VI; Tada et al. 2019. PubMed ID: 30389453). This variant is reported in 0.26% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21242731-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Benign (Aug 09, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002752807.2 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 (Jul 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005387564.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Comment: BA1
Likely benign (Nov 21, 2024) C Contributing to aggregate classification	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: SCV000777052.8 First in ClinVar: May 28, 2018 Last updated: Mar 04, 2025
Uncertain Significance (Sep 13, 2024) C Contributing to aggregate classification	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: SCV005875777.1 First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025	Comment: The APOB c.2863C>T; p.Pro955Ser variant (rs13306206, ClinVar Variation ID 431492) is reported in the literature with variable penetrance in both unaffected and dyslipidemic individuals, and … (more) The APOB c.2863C>T; p.Pro955Ser variant (rs13306206, ClinVar Variation ID 431492) is reported in the literature with variable penetrance in both unaffected and dyslipidemic individuals, and is presumed to modify the severity of familial hypercholesterolemia (Hori 2023). This variant is found predominantly in the East Asian population with an allele frequency of 0.25% (51/19954 alleles) in the Genome Aggregation Database (v2.1.1). In vitro LDL uptake assay with homozygous variant was 44% when compared to unaffected control (Hori 2023). Computational analyses predict that this variant is neutral (REVEL: 0.064). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Hori M et al. A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia. J Clin Endocrinol Metab. 2023 Jan 17. PMID: 36190978. (less)

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Reported as a single nucleotide polymorphism associated with high LDL-C levels in exome wide association studies and has been reported in association with hypertriglyceridemia (Yamada et al., 2019; Tada et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30718733, 28473662, 30389453, 33020668, 30365130)

Comment:

The APOB c.2863C>T variant is predicted to result in the amino acid substitution p.Pro955Ser. This variant has been reported in individuals with dyslipidemia, although no further evidence was provided to determine its pathogenicity (Yamada et al. 2017. PubMed ID: 28473662; Yamada et al. 2019. PubMed ID: 30365130. Table VI; Tada et al. 2019. PubMed ID: 30389453). This variant is reported in 0.26% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21242731-G-A). 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 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.2863C>T; p.Pro955Ser variant (rs13306206, ClinVar Variation ID 431492) is reported in the literature with variable penetrance in both unaffected and dyslipidemic individuals, and is presumed to modify the severity of familial hypercholesterolemia (Hori 2023). This variant is found predominantly in the East Asian population with an allele frequency of 0.25% (51/19954 alleles) in the Genome Aggregation Database (v2.1.1). In vitro LDL uptake assay with homozygous variant was 44% when compared to unaffected control (Hori 2023). Computational analyses predict that this variant is neutral (REVEL: 0.064). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Hori M et al. A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia. J Clin Endocrinol Metab. 2023 Jan 17. PMID: 36190978.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Mar 16, 2025

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.2863C>T (p.Pro955Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...