VCV000002581.29 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(7); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 2581 Accession: VCV000002581.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 44948767 (GRCh38) [ NCBI UCSC ] 19: 45452024 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 24, 2024	Aug 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000483.5:c.122A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000474.2:p.Lys41Thr	missense
NR_037932.1:n.1329A>C		non-coding transcript variant
NC_000019.10:g.44948767A>C
NC_000019.9:g.45452024A>C
NG_008837.1:g.7782A>C
	P02655:p.Lys41Thr

... more HGVS ... less HGVS

Protein change

K41T

Other names

APOC2, LYS19THR

Canonical SPDI

NC_000019.10:44948766:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00040 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00069

The Genome Aggregation Database (gnomAD) 0.00071

Trans-Omics for Precision Medicine (TOPMed) 0.00086

Exome Aggregation Consortium (ExAC) 0.00087

Links

ClinGen: CA115621 UniProtKB: P02655#VAR_000639 OMIM: 608083.0009 dbSNP: rs120074114 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APOC2		-	-	GRCh38 GRCh37	2	120
APOC4-APOC2	-	-	-	GRCh38	-	121

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Apolipoprotein c-ii variant	Pathogenic (1)	no assertion criteria provided	Mar 1, 1991	RCV000002697.2
Familial apolipoprotein C-II deficiency	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Mar 31, 2022	RCV001135899.7
not provided	Uncertain significance (6)	criteria provided, multiple submitters, no conflicts	Aug 23, 2024	RCV001551048.18
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 10, 2022	RCV003162207.2
APOC2-related disorder	Uncertain significance (1)	no assertion criteria provided	Nov 30, 2023	RCV003904797.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 31, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Familial apolipoprotein C-II deficiency Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV002764431.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: Type 2 diabetes mellitus (present) , Neuroendocrine neoplasm (present) Secondary finding: no Observation 2: Clinical Features: Hyperlipidemia (present) Secondary finding: no Observation 3: Clinical Features: Hyperlipidemia (present) , Hepatic steatosis (present) Secondary finding: no
Uncertain significance (Aug 21, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003265159.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 1782747‚ 22135386‚ 24788417‚ 33111339 Comment: 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). … (more) 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. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial apolipoprotein C-II deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001295704.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 1782747‚ 7923858‚ 1628605 Comment: 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, … (more) 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. (less)
Uncertain significance (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial apolipoprotein C-II deficiency Affected status: unknown Allele origin: unknown	Centogene AG - the Rare Disease Company Accession: SCV002059878.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Uncertain significance (Nov 10, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003911618.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Publications: PubMed (12) PubMed: 1628605‚ 1782747‚ 22135386‚ 24788417‚ 24886863‚ 25910212‚ 29100061‚ 30197986‚ 30686043‚ 32861330‚ 33111339‚ 7923858 Comment: The p.K41T variant (also known as c.122A>C), located in coding exon 2 of the APOC2 gene, results from an A to C substitution at nucleotide … (more) The p.K41T variant (also known as c.122A>C), located in coding exon 2 of the APOC2 gene, results from an A to C substitution at nucleotide position 122. The lysine at codon 41 is replaced by threonine, an amino acid with similar properties. This variant (also referred to as Lys19Thr) has been detected in the heterozygous state in individuals with and without elevated triglycerides (Hegele RA et al. Dis Markers. 1991;9(2):73-80; Menke-Möllers I et al. Electrophoresis. 1992 Apr;13(4):244-51; Zysow BR et al. Clin Genet. 1994 Jun;45(6):292-7; Johansen CT et al. Circ Cardiovasc Genet. 2012 Feb;5(1):66-72). This variant has also been detected in some individuals with amyloidosis (Sethi S et al. Kidney Int Rep, 2018 Sep;3:1193-1201; Liapis K et al. Amyloid, 2019 Mar;26:52-53; Dasari S et al. Mayo Clin Proc, 2020 09;95:1852-1864). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001771473.3 First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024	Comment: 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); … (more) 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) (less)
Uncertain significance (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004042054.11 First in ClinVar: Oct 14, 2023 Last updated: Oct 20, 2024	Comment: APOC2: PM2:Supporting, BP4 Number of individuals with the variant: 1
Uncertain significance (Feb 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408860.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (12) PubMed: 1782747‚ 22135386‚ 24788417‚ 29100061‚ 30197986‚ 30686043‚ 31589614‚ 32861330‚ 33111339‚ 36325899‚ 36555767‚ 7923858 Comment: BS1 Number of individuals with the variant: 1
Pathogenic (Mar 01, 1991)	no assertion criteria provided Method: literature only	APOLIPOPROTEIN C-II VARIANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022855.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 1782747 Comment on evidence: Hegele et al. (1991) described a lys19-to-thr mutation in 5 hyperlipidemic patients: 1 with type III, 3 with type IV, and 1 with type V … (more) Hegele et al. (1991) described a lys19-to-thr mutation in 5 hyperlipidemic patients: 1 with type III, 3 with type IV, and 1 with type V hyperlipoproteinemia. All were heterozygous for the mutation, and all were found to have both the normal apoC II isoform and the mutant isoform, whose isoelectric point was consistent with a single charge change. The presence of this mutation in unrelated hyperlipidemic patients of various racial backgrounds suggested that, in combination with other factors such as mutations in apolipoprotein E, it likely plays a role in the development of hyperlipoproteinemias. (less)
Uncertain significance (Nov 30, 2023)	no assertion criteria provided Method: clinical testing	APOC2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004722847.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920385.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962819.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

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.

Comment:

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.

Comment:

The p.K41T variant (also known as c.122A>C), located in coding exon 2 of the APOC2 gene, results from an A to C substitution at nucleotide position 122. The lysine at codon 41 is replaced by threonine, an amino acid with similar properties. This variant (also referred to as Lys19Thr) has been detected in the heterozygous state in individuals with and without elevated triglycerides (Hegele RA et al. Dis Markers. 1991;9(2):73-80; Menke-Möllers I et al. Electrophoresis. 1992 Apr;13(4):244-51; Zysow BR et al. Clin Genet. 1994 Jun;45(6):292-7; Johansen CT et al. Circ Cardiovasc Genet. 2012 Feb;5(1):66-72). This variant has also been detected in some individuals with amyloidosis (Sethi S et al. Kidney Int Rep, 2018 Sep;3:1193-1201; Liapis K et al. Amyloid, 2019 Mar;26:52-53; Dasari S et al. Mayo Clin Proc, 2020 09;95:1852-1864). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare Variants in Genes of the Cholesterol Pathway Are Present in 60% of Patients with Acute Myocardial Infarction.	Pan-Lizcano R	International journal of molecular sciences	2022	PMID: 36555767
Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine-Brief Report.	Deshotels MR	Arteriosclerosis, thrombosis, and vascular biology	2022	PMID: 36325899
Development of a new expanded next-generation sequencing panel for genetic diseases involved in dyslipidemia.	Marmontel O	Clinical genetics	2020	PMID: 33111339
Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples.	Dasari S	Mayo Clinic proceedings	2020	PMID: 32861330
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Hereditary systemic amyloidosis caused by K19T apolipoprotein C-II variant.	Liapis K	Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis	2019	PMID: 30686043
Apolipoprotein CII Amyloidosis Associated With p.Lys41Thr Mutation.	Sethi S	Kidney international reports	2018	PMID: 30197986
Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism.	Wolska A	Atherosclerosis	2017	PMID: 29100061
Widespread macromolecular interaction perturbations in human genetic disorders.	Sahni N	Cell	2015	PMID: 25910212
Post-heparin LPL activity measurement using VLDL as a substrate: a new robust method for routine assessment of plasma triglyceride lipolysis defects.	Di Filippo M	PloS one	2014	PMID: 24886863
Post-heparin LPL activity measurement using VLDL as a substrate: a new robust method for routine assessment of plasma triglyceride lipolysis defects.	Di Filippo M	PloS one	2014	PMID: 24788417
Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.	Johansen CT	Circulation. Cardiovascular genetics	2012	PMID: 22135386
The apolipoprotein C-II variant apoC-IILys19-->Thr is not associated with dyslipidemia in an affected kindred.	Zysow BR	Clinical genetics	1994	PMID: 7923858
Studies on an apolipoprotein C-II variant occurring in Caucasians.	Menke-Möllers I	Electrophoresis	1992	PMID: 1628605
An apolipoprotein CII mutation, CIILys19----Thr' identified in patients with hyperlipidemia.	Hegele RA	Disease markers	1991	PMID: 1782747
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Text-mined citations for rs120074114 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs120074114 ...