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

gnomAD frequency: 0.00153  dbSNP: rs138326449

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001401913	SCV001603751	likely benign	not provided	2023-10-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001401913	SCV001771311	uncertain significance	not provided	2022-05-16	criteria provided, single submitter	clinical testing	Canonical splice site variant; heterozygous loss-of-function variants in the APOC3 gene have been reported in association with hypotriglyceridemia and protection against cardiovascular disease; This variant is associated with the following publications: (PMID: 23701270, 25225788, 24941082, 28008009, 27114411, 24941081, 30405126, 30255797, 27146844, 29348120, 31589614, 34426522, 32041611, 28787443, 23685560, 34834584)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271410	SCV002555652	likely benign	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: APOC3 c.55+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 250966 control chromosomes (gnomAD). The observed variant frequency is approximately 70-fold of the estimated maximal expected allele frequency for a pathogenic variant in APOC3 causing Early Onset Coronary Artery Disease phenotype (2e-05), suggesting that the variant is not associated with Early Onset Coronary Artery Disease. c.55+1G>A has been reported in the literature in association with reduced levels of triglycerides and increased levels of HDL in heterozygous individuals and was shown to result in an atheroprotective lipid profile with lowered risk of coronary heart disease (Bochem_2014, Crosby_2014, Jorgensen_2014, Timpson_2014, Goyal_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23701270, 30255797, 24941081, 27114411, 32041611, 34548093, 24941082, 25225788). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002345442	SCV002648646	uncertain significance	Cardiovascular phenotype	2021-12-21	criteria provided, single submitter	clinical testing	The c.55+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the APOC3 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000148017	SCV004227982	likely pathogenic	Apolipoprotein c-III deficiency		criteria provided, single submitter	research	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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000128449	SCV000172131	protective	Coronary heart disease	2014-06-18	no assertion criteria provided	literature only
OMIM	RCV000148017	SCV000195517	pathogenic	Apolipoprotein c-III deficiency	2014-07-03	flagged submission	literature only