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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 5, 2023
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:: RCV000780859.14

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]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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protein CELLULOSE SYNTHASE INTERACTIVE 3 [Populus trichocarpa]
protein CELLULOSE SYNTHASE INTERACTIVE 3 [Populus trichocarpa]
gi|1375861509|ref|XP_024457440.1|

Protein
protein CELLULOSE SYNTHASE INTERACTIVE 3 [Vitis riparia]
protein CELLULOSE SYNTHASE INTERACTIVE 3 [Vitis riparia]
gi|1847868247|ref|XP_034674744.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000918477	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 31, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22353362, 27783906 Citation Link,
SCV001347007	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 7627691, 8141833, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 21513517, 21868016, 22294733, 23375686, 23936638, 27206935, 32591292, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000918477

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 31, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001347007

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 5, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

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

Citations

PubMed

Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China.

Chiou KR, Charng MJ.

Gene. 2012 Apr 25;498(1):100-6. doi: 10.1016/j.gene.2012.01.092. Epub 2012 Feb 14.

PubMed [citation]

PMID:: 22353362

Child-Parent Familial Hypercholesterolemia Screening in Primary Care.

Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ.

N Engl J Med. 2016 Oct 27;375(17):1628-1637.

PubMed [citation]

PMID:: 27783906

See all PubMed Citations (18)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918477.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 276418 control chromosomes (gnomAD). c.10579C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Chiou_2012, Wald_2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic" (4x) and once as "uncertain significance." Based on the evidence outlined above, the variant was 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 Color Diagnostics, LLC DBA Color Health, SCV001347007.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant (also known as p.Arg3500Trp in the mature protein) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935, 32591292). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is 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

Last Updated: Nov 10, 2024

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