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

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 17, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001837444.14

Allele description [Variation Report for NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)]

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

Gene:
APOB:apolipoprotein B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p24.1
Genomic location:
Preferred name:
NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp)
Other names:
9774C>T
HGVS:
  • NC_000002.12:g.21006289G>A
  • NG_011793.1:g.42785C>T
  • NM_000384.3:c.10579C>TMANE SELECT
  • NP_000375.2:p.Arg3527Trp
  • NP_000375.3:p.Arg3527Trp
  • NC_000002.11:g.21229161G>A
  • NM_000384.2:c.10579C>T
  • NM_000384.3(APOB):c.10579C>TMANE SELECT
  • NP_000375.2:p.R3527W
Protein change:
R3527W; Arg3500Trp
Links:
dbSNP: rs144467873
NCBI 1000 Genomes Browser:
rs144467873
Molecular consequence:
  • NM_000384.3:c.10579C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Hypercholesterolemia, autosomal dominant, type B (FHCL2)
Synonyms:
APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE; APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE; HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007751; MedGen: C1704417; OMIM: 144010
Name:
Familial hypobetalipoproteinemia 1
Synonyms:
Hypobetalipoproteinemia, normotriglyceridemic; Acanthocytosis with hypobetalipoproteinemia
Identifiers:
MONDO: MONDO:0014252; MedGen: C4551990; OMIM: 615558

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000284754Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 17, 2024) 		germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV003925320New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Pathogenic
(Sep 19, 2022) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot provided2not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia.

Gaffney D, Reid JM, Cameron IM, Vass K, Caslake MJ, Shepherd J, Packard CJ.

Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1025-9.

PubMed [citation]
PMID:
7627691

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, Koay ES, Khoo KL, Khaw MC, Sethi SK.

Clin Chem. 1997 Jun;43(6 Pt 1):916-23.

PubMed [citation]
PMID:
9191540
See all PubMed Citations (15)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284754.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From New York Genome Center, SCV003925320.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
2not provided1not providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Nov 3, 2024