Submissions for variant NM_000483.5(APOC2):c.122A>C (p.Lys41Thr)

gnomAD frequency: 0.00071  dbSNP: rs120074114

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001135899	SCV001295704	benign	Familial apolipoprotein C-II deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001551048	SCV001771473	uncertain significance	not provided	2024-08-23	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with renal amyloidosis, dyslipidemia, and acute myocardial infaraction (AMI) in published literature (PMID: 33111339, 30197986, 30686043, 36555767, 36325899); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135386, 1782747, 30686043, 34426522, 31589614, 33111339, 30197986, 36555767, 33395107, 36325899)
Centogene AG - the Rare Disease Company	RCV001135899	SCV002059878	uncertain significance	Familial apolipoprotein C-II deficiency	2019-02-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001135899	SCV002764431	uncertain significance	Familial apolipoprotein C-II deficiency	2022-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001551048	SCV003265159	uncertain significance	not provided	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 41 of the APOC2 protein (p.Lys41Thr). This variant is present in population databases (rs120074114, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of APOC2-related conditions (PMID: 1782747, 22135386, 24788417, 33111339). ClinVar contains an entry for this variant (Variation ID: 2581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003162207	SCV003911618	likely benign	Cardiovascular phenotype	2024-09-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001551048	SCV004042054	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	APOC2: PM2:Supporting, BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV001551048	SCV005408860	uncertain significance	not provided	2024-02-09	criteria provided, single submitter	clinical testing	BS1
Fulgent Genetics, Fulgent Genetics	RCV001135899	SCV005648362	uncertain significance	Familial apolipoprotein C-II deficiency	2024-02-13	criteria provided, single submitter	clinical testing
OMIM	RCV000002697	SCV000022855	pathogenic	Apolipoprotein c-ii variant	1991-03-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001551048	SCV001920385	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001551048	SCV001962819	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904797	SCV004722847	uncertain significance	APOC2-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The APOC2 c.122A>C variant is predicted to result in the amino acid substitution p.Lys41Thr. This variant was reported in individuals with apolipoprotein C2 deficiency/amyloidosis/hyperlipidemia (reported as p.Lys19Thr, Hegele et al. 1991. PubMed ID: 1782747; reported as p.K19T in Figure, Johansen et al. 2011. PubMed ID: 22135386; Sethi et al. 2018. PubMed ID: 30197986; Table S6, Marmontel. 2020. PubMed ID: 33111339). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as benign/uncertain/likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/2581/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.