VCV000040223.56 - ClinVar

NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)

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.

(28)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)

Variation ID: 40223 Accession: VCV000040223.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.1 2: 21006289 (GRCh38) [ NCBI UCSC ] 2: 21229161 (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	Jul 1, 2016	Oct 20, 2024	Jun 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000384.3(APOB):c.10579C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000384.3:c.10579C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000375.3:p.Arg3527Trp	missense
NC_000002.12:g.21006289G>A
NC_000002.11:g.21229161G>A
NG_011793.1:g.42785C>T
	NP_000375.2:p.Arg3527Trp

... more HGVS ... less HGVS

Protein change

R3527W

Other names

9774C>T

Canonical SPDI

NC_000002.12:21006288: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.

0.00040 (A)

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

1000 Genomes Project 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00017

The Genome Aggregation Database (gnomAD), exomes 0.00017

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Links

ClinGen: CA044117 dbSNP: rs144467873 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.
Hypercholesterolemia, autosomal dominant, type B	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jun 27, 2024	RCV000231844.24
Hypercholesterolemia, familial, 1	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 22, 2019	RCV000408839.16
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000494148.29
Familial hypercholesterolemia	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 5, 2023	RCV000780859.14
Homozygous familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Nov 2, 2020	RCV000844613.13
Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 17, 2024	RCV001837444.14
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jun 10, 2024	RCV002399350.10
APOB-related disorder	Pathogenic (2)	criteria provided, single submitter	Feb 1, 2022	RCV002243681.12
Familial hypobetalipoproteinemia 1	Pathogenic (1)	criteria provided, single submitter	Nov 29, 2022	RCV003147303.8

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.
Pathogenic (Apr 05, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914259.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (4) PubMed: 10388479‚ 7627691‚ 9191540‚ 9702952 Comment: Across a selection of the available literature, the APOB c.10579C>T (p.Arg3527Trp) missense variant, previously reported in the literature as p.Arg3500Trp, has been identified in a … (more) Across a selection of the available literature, the APOB c.10579C>T (p.Arg3527Trp) missense variant, previously reported in the literature as p.Arg3500Trp, has been identified in a heterozygous state in at least 33 individuals with familial hypercholesterolemia, 15 of whom were unrelated (Gaffney et al. 1995; Choong et al. 1997; Tai et al. 1998; Fisher et al. 1999). The p.Arg3527Trp variant was absent from 309 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Arg3527 is located in the LDL receptor-binding domain of the APOB protein. Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. Based on the evidence, the p.Arg3527Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713960.2 First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023	Publications: PubMed (2) PubMed: 7627691‚ 9702952 Comment: Legacy Nomenclature: p.R3500W
Likely pathogenic (Mar 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia Accession: SCV001432580.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Observation 1: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Pathogenic (Apr 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001573163.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (5) PubMed: 10388479‚ 11238294‚ 24404629‚ 27206935‚ 7627691 Comment: The c.10579C>T variant in APOB is one of the most frequent genetic changes reported in individuals with familial hypercholesterolemia-2 (FCHL2), a condition characterized by very … (more) The c.10579C>T variant in APOB is one of the most frequent genetic changes reported in individuals with familial hypercholesterolemia-2 (FCHL2), a condition characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease, beginning at 40 to 50 years of age. However, reduced penetrance of FCHL2 has been reported in persons with a heterozygous APOB pathogenic variant. This variant (rs144467873) is rare in a large population database (45/282118 total alleles; 0.016%; no homozygotes) and has an entry in ClinVar. Experiments using patient derived skin fibroblast cells that contain the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. In addition, the proliferation rate of U937 cells containing the p.Arg3527Trp substitution supplied with LDL was fourfold less than wild type controls. We consider this variant to be pathogenic. (less)
Pathogenic (Nov 02, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Homozygous familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712357.2 First in ClinVar: Apr 09, 2018 Last updated: May 29, 2021	Publications: PubMed (14) PubMed: 7627691‚ 11833852‚ 10529757‚ 20538126‚ 21376320‚ 24784157‚ 22294733‚ 9191540‚ 22353362‚ 23375686‚ 9702952‚ 10388479‚ 17964958‚ 11238294 Comment: The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the … (more) The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the majority of whom are of East Asian ancestry, and segregated with disease in at least 15 affected relatives from 4 families (Gaffney 1995 PMID: 7627691, Choong 1997 PMID: 9191540, Tai 1998 PMID: 9702952, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294, Yang 2007 PMID: 17964958, Hollandt 2012 PMID: 22294733, Chiou 2010 PMID: 20538126, Chiou 2011 PMID: 21376320, Chiou 2012 PMID: 22353362, Bertolini 2013 PMID: 23375686). This variant has been reported in ClinVar (Variation ID 40223) and has also been identified in 0.12% (25/19946) of East Asian and 0.007% (25/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294). Additionally, another variant at this position, p.Arg3527Gln, is a well-established pathogenic variant for FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, increased prevalence in affected individuals, and pathogenicity of other variants at this position. Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews, PMID: 24404629). ACMG/AMP Criteria applied: PS4_Strong; PP1_Strong, PS3_Supporting, PM5. (less) Number of individuals with the variant: 5
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501489.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (19) PubMed: 7627691‚ 23375686‚ 30592178‚ 30217213‚ 9191540‚ 10388479‚ 32719484‚ 30291343‚ 30420299‚ 30586733‚ 24784157‚ 30971288‚ 33740630‚ 33418990‚ 29353225‚ 28965616‚ 34037665‚ 9702952‚ 31447099 Number of individuals with the variant: 2 Secondary finding: no
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518482.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Feb 03, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000583115.5 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: Reported as a common cause of FH among East Asians (Andersen et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more) Reported as a common cause of FH among East Asians (Andersen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the variant reduced APOB capacity for binding, uptake, and degradation of LDL (Fisher et al., 1999); Also reported as R3500W due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 9191540, 30217213, 10529757, 31686828, 23375686, 24784157, 7627691, 27919345, 28965616, 30971288, 30592178, 26415676, 24234650, 23936638, 11238294, 11833852, 30420299, 30586733, 30291343, 20538126, 28235710, 29399563, 22294733, 29353225, 31447099, 9702952, 31345425, 10388479, 27765764, 27783906, 16250003, 34037665, 7718024, 34220717, 33418990, 33740630, 32719484, 34426522) (less)
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835980.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypobetalipoproteinemia 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836041.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Sep 19, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Familial hypobetalipoproteinemia 1 Hypercholesterolemia, autosomal dominant, type B Affected status: yes Allele origin: germline	New York Genome Center Accession: SCV003925320.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: The c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene substitutes a well conserved Arginine for Tryptophan at amino acid 3527/4564 (exon 26/29). It is found … (more) The c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene substitutes a well conserved Arginine for Tryptophan at amino acid 3527/4564 (exon 26/29). It is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency 8.54e-5 (gnomADv3.1.2, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant is also referred to as p.Arg3500Trp in literature based off of annotation from mature protein. In silico algorithms predict this variant to be Pathogenic (REVEL;score:0.8539) to the function of the canonical protein. This variant is reported in ClinVar as Pathogenic / Likely Pathogenic (VarID:40223), and has been reported in many affected individuals with familial hypercholesterolemia, and has been shown to segregate with hypercholesterolemia in multiple affected families [PMID:27206935, 21376320, 9702952, 7627691, others]. Functional studies suggest this variant reduces binding, uptake, and degradation of LDL [PMID:7627691,11238294]. Given its presence in many affected individuals in the literature in which it segregates with disease, functional studies showing altered activity, and its low frequency in population databases, the c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene is reported as Pathogenic. (less) Observation 1: Clinical Features: Hyperlipidemia (present) , Diabetes mellitus (present) Secondary finding: no Observation 2: Clinical Features: Hyperlipidemia (present) Secondary finding: no
Pathogenic (Sep 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018316.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004822899.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (15) PubMed: 7627691‚ 8141833‚ 9191540‚ 9702952‚ 10388479‚ 11238294‚ 16250003‚ 21376320‚ 21513517‚ 21868016‚ 22294733‚ 23375686‚ 23936638‚ 27206935‚ 32591292 Comment: This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests … (more) This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 13
Pathogenic (Jun 10, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002712483.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (14) PubMed: 2563166‚ 7627691‚ 9191540‚ 9702952‚ 10388479‚ 11238294‚ 16250003‚ 21376320‚ 22294733‚ 23375686‚ 23936638‚ 24784157‚ 27206935‚ 30592178 Comment: The c.10579C>T (p.R3527W) alteration is located in exon 26 (coding exon 26) of the APOB gene. This alteration results from a C to T substitution … (more) The c.10579C>T (p.R3527W) alteration is located in exon 26 (coding exon 26) of the APOB gene. This alteration results from a C to T substitution at nucleotide position 10579, causing the arginine (R) at amino acid position 3527 to be replaced by a tryptophan (W). Based on the available evidence, the APOB c.10579C>T (p.R3527W) alteration is classified as pathogenic for autosomal dominant APOB-related familial hypercholesterolemia; however, its clinical significance for autosomal recessive APOB-related hypobetalipoproteinemia is uncertain. Based on data from the Genome Aggregation Database (gnomAD), the APOB c.10579C>T alteration was observed in 0.02% (45/282,118) of total alleles studied, with a frequency of 0.13% (25/19,946) in the East Asian subpopulation. This alteration, also known as p.R3500W, has been reported in multiple individuals and families with hyperlipidemia from varying ethnic backgrounds (Gaffney, 1995; Choong, 1997; Fisher, 1999; Tai, 1998; Tai, 2001; Chiou, 2011; Bertolini, 2013) and has been reported as a common cause of disease in Asian populations (Chiou, 2011; Chiou, 2016; Chan, 2019). In addition, two alterations at the same codon, p.R3527Q and p.R3527L (reported as p.R3500Q and p.R3500L), have also been associated with familial hypercholesterolemia (Soria, 1989; Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. In vitro studies have reported this alteration to attenuate protein function (Gaffney, 1995; Tai, 2001). The p.R3527W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jul 31, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918477.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (2) PubMed: 22353362‚ 27783906 Comment: Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico … (more) Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 276418 control chromosomes (gnomAD). c.10579C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Chiou_2012, Wald_2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic" (4x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Aug 22, 2019)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484822.2 First in ClinVar: Dec 18, 2016 Last updated: Sep 10, 2019	Publications: PubMed (1) PubMed: 27765764 Number of individuals with the variant: 1
Pathogenic (Apr 27, 2021)	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: SCV002046141.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Publications: PubMed (22) PubMed: 9702952‚ 9191540‚ 7627691‚ 27783906‚ 27765764‚ 26415676‚ 2563166‚ 24784157‚ 24234650‚ 23936638‚ 23375686‚ 22353362‚ 22294733‚ 21862702‚ 21376320‚ 20538126‚ 17964958‚ 16250003‚ 11833852‚ 11238294‚ 10529757‚ 10388479 Comment: This variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 26415676 (2015) and 27765764 (2015)). This variant segregates with disease … (more) This variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 26415676 (2015) and 27765764 (2015)). This variant segregates with disease in multiple families (PMID: 27783906 (2016), 11238294 (2001), and 10388479 (1999)). Assessment of experimental evidence regarding the effect of this variant suggests it is detrimental to normal function (PMID: 11238294 (2001), 10388479 (1999), and 7627691 (1995)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (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: SCV001422753.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022	Publications: PubMed (5) PubMed: 9486979‚ 27206935‚ 20538126‚ 17087781‚ 7627691 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3823803d-701a-4fd1-9e38-00011e8dcc50 Comment: The p.Arg3527Trp variant in APOB has been reported in at least 47 individuals with hypercholesterolemia, segregated with disease in 10 individuals from 2 families (PMID: … (more) The p.Arg3527Trp variant in APOB has been reported in at least 47 individuals with hypercholesterolemia, segregated with disease in 10 individuals from 2 families (PMID: 27206935, 17087781, 20538126), and has been identified in 0.1253% (25/19946) of East Asian chromosomes, 0.03594% (11/30604) of South Asian chromosomes, and 0.007002% (9/128542) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144467873). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Animal models in mice have shown that this variant causes hypercholesterolemia (PMID: 9486979). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional pathogenic/likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg3527Gln and p.Arg3527Leu, have been reported in association with hypercholesterolemia in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 17890, 440523; PMID: 9486979, 23369702, 28428224). Additionally, the p.Arg3527Trp variant is located in a region of APOB that is essential to protein folding and stability, suggesting that this variant is a functional domain and supports pathogenicity (PMID: 9486979). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on prevalence of the variant and cosegregation in affected individuals, the location of the variant in a functional domain, and animal models demonstrating a deficient protein. ACMG/AMP Criteria applied: PS4, PP11_strong, PM5, PM1, PS3_moderate, PP3 (Richards 2015). (less)
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	APOB-related disorder Affected status: unknown Allele origin: unknown	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002515289.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Publications: PubMed (1) PubMed: 36474027 Number of individuals with the variant: 1
Pathogenic (Apr 05, 2023)	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: SCV001347007.4 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 7627691‚ 8141833‚ 9191540‚ 9702952‚ 10388479‚ 11238294‚ 16250003‚ 21376320‚ 21513517‚ 21868016‚ 22294733‚ 23375686‚ 23936638‚ 27206935‚ 32591292 Comment: This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests … (more) This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 17, 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: SCV000284754.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024	Publications: PubMed (15) PubMed: 28492532‚ 7627691‚ 9191540‚ 9702952‚ 11238294‚ 16250003‚ 21376320‚ 22294733‚ 27206935‚ 23375686‚ 23936638‚ 26415676‚ 2563166‚ 10388479‚ 24234650 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3527 of the APOB protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3527 of the APOB protein (p.Arg3527Trp). This variant is present in population databases (rs144467873, gnomAD 0.1%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 27206935). It is commonly reported in individuals of East Asian ancestry (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 26415676, 27206935). This variant is also known as R3500W. ClinVar contains an entry for this variant (Variation ID: 40223). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. This variant disrupts the p.Arg3527 amino acid residue in APOB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2563166, 10388479, 11238294, 24234650). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, type B Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005077730.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Comment: ACMG Criteria: PS3, PS4, PM2_P, PM5, PP1, PP3, PP5; Variant was found in heterozygous state Clinical Features: 2:1 atrioventricular block (present) , Bradycardia (present) , Ventricular arrhythmia (present) , Fatigue (present) , Hypercholesterolemia (present) , Arthralgia (present) , Male sexual dysfunction (present)
Pathogenic (Jan 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: SCV004698727.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: APOB: PP1:Strong, PS4, PM5, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000605967.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016
Pathogenic (May 03, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000803730.1 First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017
Pathogenic (Jun 07, 2024)	no assertion criteria provided Method: clinical testing	APOB-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004725717.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The APOB c.10579C>T variant is predicted to result in the amino acid substitution p.Arg3527Trp. This variant (also known as p.Arg3500Trp) has been reported in many … (more) The APOB c.10579C>T variant is predicted to result in the amino acid substitution p.Arg3527Trp. This variant (also known as p.Arg3500Trp) has been reported in many patients with autosomal dominant hypercholesterolemia (see for example Gaffney et al. 1995. PubMed ID: 7627691; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616). Additionally, different substitutions of the same amino acid (p.Arg3527Gln and p.Arg3527Leu) have been reported in many patients with hypercholesterolemia (see for example Soria et al. 1989. PubMed ID: 2563166; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616; Fouchier et al. 2005. PubMed ID: 16250003), suggesting that the amino acid residue p.Arg3527 is important for proper APOB protein function. This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Hypercholesterolemia, autosomal dominant, type B Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000490149.2 First in ClinVar: Jul 01, 2016 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 21862702 BookShelf: NBK174884 BookShelf: NBK174884 Geographic origin: Asia
Uncertain significance (Mar 01, 2016)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: research Reason: Claim with insufficient supporting evidence Source: ClinGen	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Fundacion Hipercolesterolemia Familiar Study: SAFEHEART Accession: SCV000607383.1 First in ClinVar: Dec 18, 2016 Last updated: Dec 18, 2016	Publications: PubMed (1) PubMed: 7627691 Observation 1: Comment on evidence: %MAF(ExAC):0.01651 Observation 2: Comment on evidence: Htz patient LDL, U937 cells proliferation assays Result: 50% cells proliferation
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Comment:

Across a selection of the available literature, the APOB c.10579C>T (p.Arg3527Trp) missense variant, previously reported in the literature as p.Arg3500Trp, has been identified in a heterozygous state in at least 33 individuals with familial hypercholesterolemia, 15 of whom were unrelated (Gaffney et al. 1995; Choong et al. 1997; Tai et al. 1998; Fisher et al. 1999). The p.Arg3527Trp variant was absent from 309 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Arg3527 is located in the LDL receptor-binding domain of the APOB protein. Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. Based on the evidence, the p.Arg3527Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The c.10579C>T variant in APOB is one of the most frequent genetic changes reported in individuals with familial hypercholesterolemia-2 (FCHL2), a condition characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease, beginning at 40 to 50 years of age. However, reduced penetrance of FCHL2 has been reported in persons with a heterozygous APOB pathogenic variant. This variant (rs144467873) is rare in a large population database (45/282118 total alleles; 0.016%; no homozygotes) and has an entry in ClinVar. Experiments using patient derived skin fibroblast cells that contain the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. In addition, the proliferation rate of U937 cells containing the p.Arg3527Trp substitution supplied with LDL was fourfold less than wild type controls. We consider this variant to be pathogenic.

Comment:

The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the majority of whom are of East Asian ancestry, and segregated with disease in at least 15 affected relatives from 4 families (Gaffney 1995 PMID: 7627691, Choong 1997 PMID: 9191540, Tai 1998 PMID: 9702952, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294, Yang 2007 PMID: 17964958, Hollandt 2012 PMID: 22294733, Chiou 2010 PMID: 20538126, Chiou 2011 PMID: 21376320, Chiou 2012 PMID: 22353362, Bertolini 2013 PMID: 23375686). This variant has been reported in ClinVar (Variation ID 40223) and has also been identified in 0.12% (25/19946) of East Asian and 0.007% (25/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294). Additionally, another variant at this position, p.Arg3527Gln, is a well-established pathogenic variant for FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, increased prevalence in affected individuals, and pathogenicity of other variants at this position. Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews, PMID: 24404629). ACMG/AMP Criteria applied: PS4_Strong; PP1_Strong, PS3_Supporting, PM5.

Comment:

Reported as a common cause of FH among East Asians (Andersen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the variant reduced APOB capacity for binding, uptake, and degradation of LDL (Fisher et al., 1999); Also reported as R3500W due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 9191540, 30217213, 10529757, 31686828, 23375686, 24784157, 7627691, 27919345, 28965616, 30971288, 30592178, 26415676, 24234650, 23936638, 11238294, 11833852, 30420299, 30586733, 30291343, 20538126, 28235710, 29399563, 22294733, 29353225, 31447099, 9702952, 31345425, 10388479, 27765764, 27783906, 16250003, 34037665, 7718024, 34220717, 33418990, 33740630, 32719484, 34426522)

Comment:

The c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene substitutes a well conserved Arginine for Tryptophan at amino acid 3527/4564 (exon 26/29). It is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency 8.54e-5 (gnomADv3.1.2, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant is also referred to as p.Arg3500Trp in literature based off of annotation from mature protein. In silico algorithms predict this variant to be Pathogenic (REVEL;score:0.8539) to the function of the canonical protein. This variant is reported in ClinVar as Pathogenic / Likely Pathogenic (VarID:40223), and has been reported in many affected individuals with familial hypercholesterolemia, and has been shown to segregate with hypercholesterolemia in multiple affected families [PMID:27206935, 21376320, 9702952, 7627691, others]. Functional studies suggest this variant reduces binding, uptake, and degradation of LDL [PMID:7627691,11238294]. Given its presence in many affected individuals in the literature in which it segregates with disease, functional studies showing altered activity, and its low frequency in population databases, the c.10579C>T (p.Arg3527Trp) variant identified in the APOB gene is reported as Pathogenic.

Comment:

This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic.

Comment:

The c.10579C>T (p.R3527W) alteration is located in exon 26 (coding exon 26) of the APOB gene. This alteration results from a C to T substitution at nucleotide position 10579, causing the arginine (R) at amino acid position 3527 to be replaced by a tryptophan (W). Based on the available evidence, the APOB c.10579C>T (p.R3527W) alteration is classified as pathogenic for autosomal dominant APOB-related familial hypercholesterolemia; however, its clinical significance for autosomal recessive APOB-related hypobetalipoproteinemia is uncertain. Based on data from the Genome Aggregation Database (gnomAD), the APOB c.10579C>T alteration was observed in 0.02% (45/282,118) of total alleles studied, with a frequency of 0.13% (25/19,946) in the East Asian subpopulation. This alteration, also known as p.R3500W, has been reported in multiple individuals and families with hyperlipidemia from varying ethnic backgrounds (Gaffney, 1995; Choong, 1997; Fisher, 1999; Tai, 1998; Tai, 2001; Chiou, 2011; Bertolini, 2013) and has been reported as a common cause of disease in Asian populations (Chiou, 2011; Chiou, 2016; Chan, 2019). In addition, two alterations at the same codon, p.R3527Q and p.R3527L (reported as p.R3500Q and p.R3500L), have also been associated with familial hypercholesterolemia (Soria, 1989; Fouchier, 2005). This amino acid position is highly conserved in available vertebrate species. In vitro studies have reported this alteration to attenuate protein function (Gaffney, 1995; Tai, 2001). The p.R3527W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 276418 control chromosomes (gnomAD). c.10579C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Chiou_2012, Wald_2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic" (4x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 26415676 (2015) and 27765764 (2015)). This variant segregates with disease in multiple families (PMID: 27783906 (2016), 11238294 (2001), and 10388479 (1999)). Assessment of experimental evidence regarding the effect of this variant suggests it is detrimental to normal function (PMID: 11238294 (2001), 10388479 (1999), and 7627691 (1995)). Based on the available information, this variant is classified as pathogenic.

Comment:

The p.Arg3527Trp variant in APOB has been reported in at least 47 individuals with hypercholesterolemia, segregated with disease in 10 individuals from 2 families (PMID: 27206935, 17087781, 20538126), and has been identified in 0.1253% (25/19946) of East Asian chromosomes, 0.03594% (11/30604) of South Asian chromosomes, and 0.007002% (9/128542) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144467873). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Animal models in mice have shown that this variant causes hypercholesterolemia (PMID: 9486979). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional pathogenic/likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg3527Gln and p.Arg3527Leu, have been reported in association with hypercholesterolemia in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 17890, 440523; PMID: 9486979, 23369702, 28428224). Additionally, the p.Arg3527Trp variant is located in a region of APOB that is essential to protein folding and stability, suggesting that this variant is a functional domain and supports pathogenicity (PMID: 9486979). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on prevalence of the variant and cosegregation in affected individuals, the location of the variant in a functional domain, and animal models demonstrating a deficient protein. ACMG/AMP Criteria applied: PS4, PP11_strong, PM5, PM1, PS3_moderate, PP3 (Richards 2015).

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3527 of the APOB protein (p.Arg3527Trp). This variant is present in population databases (rs144467873, gnomAD 0.1%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 27206935). It is commonly reported in individuals of East Asian ancestry (PMID: 7627691, 9191540, 9702952, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 26415676, 27206935). This variant is also known as R3500W. ClinVar contains an entry for this variant (Variation ID: 40223). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. This variant disrupts the p.Arg3527 amino acid residue in APOB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2563166, 10388479, 11238294, 24234650). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The APOB c.10579C>T variant is predicted to result in the amino acid substitution p.Arg3527Trp. This variant (also known as p.Arg3500Trp) has been reported in many patients with autosomal dominant hypercholesterolemia (see for example Gaffney et al. 1995. PubMed ID: 7627691; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616). Additionally, different substitutions of the same amino acid (p.Arg3527Gln and p.Arg3527Leu) have been reported in many patients with hypercholesterolemia (see for example Soria et al. 1989. PubMed ID: 2563166; Bertolini et al. 2013. PubMed ID: 23375686; Pirillo et al. 2017. PubMed ID: 28965616; Fouchier et al. 2005. PubMed ID: 16250003), suggesting that the amino acid residue p.Arg3527 is important for proper APOB protein function. This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.

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
High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.	Belanger Deloge R	European journal of human genetics : EJHG	2023	PMID: 36474027
Familial Hypercholesterolemia.	Adam MP	-	2022	PMID: 24404629
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.	Sturm AC	JAMA cardiology	2021	PMID: 34037665
Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020.	Leren TP	Atherosclerosis	2021	PMID: 33740630
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.	Meshkov A	Genes	2021	PMID: 33418990
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
The first Japanese cases of familial hypercholesterolemia due to a known pathogenic APOB gene variant, c.10580 G>A: p.(Arg3527Gln).	Hori M	Journal of clinical lipidology	2020	PMID: 32591292
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction.	Lee C	Lipids in health and disease	2019	PMID: 30971288
Genetic variations in familial hypercholesterolemia and cascade screening in East Asians.	Chan ML	Molecular genetics & genomic medicine	2019	PMID: 30592178
Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.	Khera AV	Circulation	2019	PMID: 30586733
1 in 38 individuals at risk of a dominant medically actionable disease.	Haer-Wigman L	European journal of human genetics : EJHG	2019	PMID: 30291343
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
Secondary findings in 421 whole exome-sequenced Chinese children.	Chen W	Human genomics	2018	PMID: 30217213
Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.	Pek SLT	Atherosclerosis	2018	PMID: 29353225
Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study.	Pirillo A	Atherosclerosis. Supplements	2017	PMID: 28965616
Child-Parent Familial Hypercholesterolemia Screening in Primary Care.	Wald DS	The New England journal of medicine	2016	PMID: 27783906
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.	Wang J	Arteriosclerosis, thrombosis, and vascular biology	2016	PMID: 27765764
Genetic diagnosis of familial hypercholesterolemia in Han Chinese.	Chiou KR	Journal of clinical lipidology	2016	PMID: 27206935
Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population.	Radovica-Spalvina I	BMC medical genetics	2015	PMID: 26415676
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.	Lawrence L	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24784157
Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia.	Alves AC	Human molecular genetics	2014	PMID: 24234650
Quality assessment of the genetic test for familial hypercholesterolemia in the Netherlands.	Kindt I	Cholesterol	2013	PMID: 23936638
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.	Bertolini S	Atherosclerosis	2013	PMID: 23375686
Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China.	Chiou KR	Gene	2012	PMID: 22353362
Microfluidic amplification as a tool for massive parallel sequencing of the familial hypercholesterolemia genes.	Hollants S	Clinical chemistry	2012	PMID: 22294733
Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family.	Garcia-Garcia AB	Atherosclerosis	2011	PMID: 21868016
Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk.	Calandra S	Journal of lipid research	2011	PMID: 21862702
Familial hypercholesterolemia: the lipids or the genes?	Fahed AC	Nutrition & metabolism	2011	PMID: 21513517
Array-based resequencing for mutations causing familial hypercholesterolemia.	Chiou KR	Atherosclerosis	2011	PMID: 21376320
Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.	Chiou KR	The American journal of cardiology	2010	PMID: 20538126
LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population.	Yang KC	Journal of the Formosan Medical Association = Taiwan yi zhi	2007	PMID: 17964958
Identification and characterization of novel low-density lipoprotein receptor mutations of familial hypercholesterolaemia patients in Taiwan.	Charng MJ	European journal of clinical investigation	2006	PMID: 17087781
Update of the molecular basis of familial hypercholesterolemia in The Netherlands.	Fouchier SW	Human mutation	2005	PMID: 16250003
Italian familial defective apolipoprotein B patients share a unique haplotype with other Caucasian patients.	Cefalù AB	Clinical and experimental medicine	2001	PMID: 11833852
Compound heterozygous familial hypercholesterolemia and familial defective apolipoprotein B-100 produce exaggerated hypercholesterolemia.	Tai ES	Clinical chemistry	2001	PMID: 11238294
LDL receptor mutations and ApoB mutations are not risk factors for ischemic cerebrovascular disease of the young, but lipids and lipoproteins are.	Frikke-Schmidt R	European journal of neurology	1999	PMID: 10529757
Mutations in the apolipoprotein (apo) B-100 receptor-binding region: detection of apo B-100 (Arg3500-->Trp) associated with two new haplotypes and evidence that apo B-100 (Glu3405-->Gln) diminishes receptor-mediated uptake of LDL.	Fisher E	Clinical chemistry	1999	PMID: 10388479
Identification and haplotype analysis of apolipoprotein B-100 Arg3500-->Trp mutation in hyperlipidemic Chinese.	Tai DY	Clinical chemistry	1998	PMID: 9702952
Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100.	Boren J	The Journal of clinical investigation	1998	PMID: 9486979
Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500-->tryptophan mutation associated with a unique haplotype.	Choong ML	Clinical chemistry	1997	PMID: 9191540
Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia.	Gaffney D	Arteriosclerosis, thrombosis, and vascular biology	1995	PMID: 7627691
Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia.	Myant NB	Atherosclerosis	1993	PMID: 8141833
Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.	Soria LF	Proceedings of the National Academy of Sciences of the United States of America	1989	PMID: 2563166
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3823803d-701a-4fd1-9e38-00011e8dcc50	-	-	-	-
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Text-mined citations for rs144467873 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144467873 ...