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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 30, 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:: RCV001837437.13

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:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541940	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 2563166, 9105560, 10388479, 18222178, 18325181, 21059979, 21868016, 23375686, 24404629, 11115503, 15797858, 7627691, 28492532
SCV003925306	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Sep 16, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541940

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV003925306

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Pathogenic
(Sep 16, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical 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 ligand-defective apolipoprotein B-100: detection, biochemical features and haplotype analysis of the R3531C mutation in the UK.

Wenham PR, Henderson BG, Penney MD, Ashby JP, Rae PW, Walker SW.

Atherosclerosis. 1997 Mar 21;129(2):185-92.

PubMed [citation]

PMID:: 9105560

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000541940.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3527 of the APOB protein (p.Arg3527Gln). This variant is present in population databases (rs5742904, gnomAD 0.06%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 2563166, 9105560, 10388479, 18222178, 18325181, 21059979, 21868016, 23375686, 24404629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17890). 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. Experimental studies have shown that this missense change affects APOB function (PMID: 11115503, 15797858). 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: 7627691). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center, SCV003925306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The c.10580G>A variant has previously been reported in multiple individuals with familial hypercholesterolemia [PMID: 24404629] and has been shown to segregate with hypercholesterolemia in multiple families [PMID: 2563166, 8254047, 21868016]. This variant is reported as one of the two most common variants associated with familial hypercholesterolemia, particularly in individuals of European ancestry [PMID: 24404629]. Multiple independent laboratories have deposited this variant as Pathogenic/Likely Pathogenic in the ClinVar database (Variation ID: 17890). The c.10580G>A variant is observed in 328 alleles (0.0556% minor allele frequency with 5homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population and pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causingLDLR or PCSK9 variants [PMID: 24404629]. The c.10580G>A variant is located in exon 26 of this 29-exon gene and is predicted to replace an evolutionarilyconserved arginine amino acid with glutamine at position 3527 in the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg3527Gln) variant [(CADD v1.6 = 28, REVEL = 0.735)]. Functional studies have demonstrated that this variant affects APOB protein conformation and impairs its binding to the LDLR protein [PMID: 8254047, 9486979, 10388479, 11115503, 15797858, 26643808]. A different amino acid change at this codon p.(Arg3527Gln) has been reported in ClinVar [ClinVar ID: 40223] as Pathogenic. Moreover, a different missense variant p.(Arg3527Leu) has been reported in individuals with familial hypercholesterolemia [PMID:16250003, 33269076]. Based on available evidence this c.10580G>A p.(Arg3527Gln) variant identified in APOB is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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