NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) AND APOB-related disorder

Germline classification:: Pathogenic (2 submissions)
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:: RCV004528126.2

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]

Condition(s)

Name:: APOB-related disorder
Synonyms:: APOB-Related Disorders; APOB-related condition
Identifiers:

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rab-like protein 2A isoform X5 [Homo sapiens]
rab-like protein 2A isoform X5 [Homo sapiens]
gi|2462569565|ref|XP_054196247.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046030	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004105374	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (May 31, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004046030

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004105374

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(May 31, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046030.1

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

Description

This variant is also known in the literature as p.Arg3500Gln (PMID: 27919345). This variant has been previously reported as heterozygous change in patients with hypercholesterolemia (PMID: 9105560, 21059979, 18325181, 18222178, 10388479, 23375686, 2563166, 21868016). Experimental studies have shown that this missense change disturbs the APOB protein conformation, therefore reducing its ability to act as inhibitor of the LDL receptor (PMID: 11115503, 15797858). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (83/282162), and one homozygous individual is also reported. The c.10580G>A (p.Arg3527Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.10580G>A (p.Arg3527Gln) variant is classified as Pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004105374.3

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

Description

The APOB c.10580G>A variant is predicted to result in the amino acid substitution p.Arg3527Gln. This variant was identified and characterized in the 1980s (aka p.Arg3500Gln, Innerarity et al. 1987. PubMed ID: 3477815; Soria et al. 1989. PubMed ID: 2563166). It is now recognized as the most common pathogenic variant in APOB for autosomal dominant familial hypercholesterolemia (reviewed by Varret et al. 2008. PubMed ID: 18028451). The p.Arg3527Gln substitution has been shown to reduce the binding affinity of LDL receptors to 30% of normal values (Innerarity et al. 1987. PubMed ID: 3477815). This variant is reported in 0.059% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted 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

Last Updated: Nov 10, 2024

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