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NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) AND Homozygous familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 2, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000844612.13

Allele description [Variation Report for NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)]

NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)

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.10580G>A (p.Arg3527Gln)
Other names:
R3500Q; 9775G>A
HGVS:
  • NC_000002.12:g.21006288C>T
  • NG_011793.1:g.42786G>A
  • NM_000384.3:c.10580G>AMANE SELECT
  • NP_000375.2:p.Arg3527Gln
  • NP_000375.3:p.Arg3527Gln
  • NC_000002.11:g.21229160C>T
  • NM_000384.2:c.10580G>A
  • NM_000384.3(APOB):c.10580G>AMANE SELECT
  • NP_000375.2:p.R3527Q
  • p.ARG3527GLN
Protein change:
R3527Q; Arg3500Gln
Links:
OMIM: 107730.0009
Molecular consequence:
  • NM_000384.3:c.10580G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
50

Condition(s)

Name:
Homozygous familial hypercholesterolemia
Synonyms:
Familial hypercholesterolemia - homozygous
Identifiers:
MONDO: MONDO:0018328; MedGen: C0342881

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000271309Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Nov 2, 2020) 		germlineclinical testing

PubMed (43)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown5250not providednot providednot providedclinical testing

Citations

PubMed

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ.

Proc Natl Acad Sci U S A. 1989 Jan;86(2):587-91.

PubMed [citation]
PMID:
2563166
PMCID:
PMC286517

Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease.

Tybjaerg-Hansen A, Humphries SE.

Atherosclerosis. 1992 Oct;96(2-3):91-107. Review.

PubMed [citation]
PMID:
1466657
See all PubMed Citations (43)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271309.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided52not providednot providedclinical testing PubMed (43)

Description

The p.Arg3527Gln variant in APOB is a well-established pathogenic variant that is mainly found in individuals of European descent. It has been previously reported in >500 individuals with familial hypercholesterolemia (FH) and segregated with disease in >50 affected relatives (Soria 1989 PMID: 2563166, März 1993 PMID: 8254047, Leren 1997 PMID: 9104431, Ludwig 1990 PMID: 1977310, Bednarska-Makaruk 2001 PMID: 11781700, Horvath 2001 PMID: 11494965, Kalina 2001 PMID: 11137107). It has also been reported by other clinical laboratories in ClinVar (Variation ID 17890) and has been identified in 0.06% (76/128568) of European chromosomes, including 1 homozygote, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia based upon presence in multiple affected individuals and segregation studies. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided52not provided50not provided

Last Updated: May 7, 2024