NM_000040.3(APOC3):c.55+1G>A AND Apolipoprotein c-III deficiency

Germline classification:: Likely 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:: RCV000148017.9

Allele description [Variation Report for NM_000040.3(APOC3):c.55+1G>A]

NM_000040.3(APOC3):c.55+1G>A

Gene:

APOC3:apolipoprotein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_000040.3(APOC3):c.55+1G>A

Other names:

IVS2+1G>A

HGVS:

NC_000011.10:g.116830638G>A
NG_008949.1:g.5731G>A
NM_000040.3:c.55+1G>AMANE SELECT
NC_000011.9:g.116701354G>A
NM_000040.1:c.55+1G>A

Nucleotide change:

IVS2+1G-A (rs138326449)

Links:

OMIM: 107720.0004; dbSNP: rs138326449

NCBI 1000 Genomes Browser:

rs138326449

Molecular consequence:

NM_000040.3:c.55+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Apolipoprotein c-III deficiency
Synonyms:: Hyperalphalipoproteinemia 2
Identifiers:: MONDO: MONDO:0013534; MedGen: C3151467; OMIM: 614028

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195517	OMIM	no assertion criteria provided	Pathogenic (Jul 3, 2014)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 24941081, 24941082, 25962519
SCV004227982	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (2) [See all records that cite these PMIDs] 36876364, 23701270

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000195517

OMIM

no assertion criteria provided

Pathogenic
(Jul 3, 2014)

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV004227982

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

research

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	1	not provided	not provided	yes	research

Citations

PubMed

Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute., Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, et al.

N Engl J Med. 2014 Jul 3;371(1):22-31. doi: 10.1056/NEJMoa1307095. Epub 2014 Jun 18.

PubMed [citation]

PMID:: 24941081
PMCID:: PMC4180269

Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.

Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A.

N Engl J Med. 2014 Jul 3;371(1):32-41. doi: 10.1056/NEJMoa1308027. Epub 2014 Jun 18.

PubMed [citation]

PMID:: 24941082

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000195517.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

By sequencing the protein-coding regions of 18,666 genes in 3,734 individuals of European or African ancestry to search for genes associated with plasma triglyceride levels, the TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute (2014) identified a splice site mutation in the APOC3 gene, IVS2+1G-A, that was associated with decreased plasma triglyceride levels and decreased levels of apoC-III (614028). The authors identified 10 heterozygous carriers of the IVS2+1G-A mutation; their mean triglyceride level was 71.0 mg/dl, with a mean HDL cholesterol level of 59.6 mg/dl and mean LDL cholesterol level of 111.7 mg/dl.

Among 75,725 study participants, Jorgensen et al. (2014) identified 209 heterozygotes for the IVS2+1G-A variant and found that their mean triglyceride levels were 44% lower than those of noncarriers (p less than 0.001).

In a study of 3,202 individuals from 2 deeply phenotyped British cohorts, Timpson et al. (2014) found association of a rare (minor allele frequency approximately 0.25% in the United Kingdom) variant in the APOC3 gene, rs138326449A, with decreased plasma triglyceride levels (-1.43 SD per minor allele, p = 8.0 x 10(-8)). The SNP represents a G-to-A transition at the +1 position of APOC3 intron 2 (IVS2+1G-A). Timpson et al. (2014) replicated this finding in 12,831 participants from 5 additional samples of Northern and Southern European origin.

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

From Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences, SCV004227982.2

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

Description

This APOC3 splicing variant NM_000040.3:c.55+1G>A (rs138326449) was described for the first time in PMID: 23701270 and has been associated with decreased plasma triglyceride and apoC-III levels. Normally it has been reported to show an atheroprotective effect (see also PMID: 24941081; PMID: 24941081; PMID: 25225788; PMID: 25962519; PMID: 27114411; PMID: 30255797; PMID: 32041611; PMID: 34548093). We report this variant in a 57-year-old male patient with combined hypolipidaemia, who presented with premature peripheral vascular disease, and also in one of his two sons, 32-years-old. Both individuals manifested decreased TG levels (between the 10th and 25th centiles). The atheroprotective effect has not been seen in the patients, most likely because they also carried a novel ABCA1 variant NM_005502.4:c.1857_1858delinsAT, possibly responsible for their decreased HDL levels (see PMID: 36876364). The effect of the APOC3 splicing variant on TG levels is further confirmed by the evidence, that the second son, 32-years-old, who carried the ABCA1 variant but not the APOC3 variant, had TG values between 75th and 90th centiles. This variant is listed as a disease-causing in the HGMD database (CS138510) and GnomAD Exomes Version: 4.0 indicates the frequency of ƒ = 0.00199.

#	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		2	not provided	1	not provided

Last Updated: Mar 10, 2024

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