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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004046030Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenicgermlineclinical testing

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

SCV004105374PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(May 31, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

From PreventionGenetics, part of Exact Sciences, SCV004105374.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

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

Last Updated: Oct 8, 2024