VCV000004403.13 - ClinVar

NM_001371904.1(APOA5):c.56C>G (p.Ser19Trp)

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.

(6)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001371904.1(APOA5):c.56C>G (p.Ser19Trp)

Variation ID: 4403 Accession: VCV000004403.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 116791691 (GRCh38) [ NCBI UCSC ] 11: 116662407 (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	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001371904.1:c.56C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358833.1:p.Ser19Trp	missense
NM_001166598.2:c.56C>G	NP_001160070.1:p.Ser19Trp	missense
NM_052968.5:c.56C>G	NP_443200.2:p.Ser19Trp	missense
NC_000011.10:g.116791691G>C
NC_000011.9:g.116662407G>C
NG_015894.2:g.5730C>G
NG_051344.1:g.746G>C
	Q6Q788:p.Ser19Trp

... more HGVS ... less HGVS

Protein change

S19W

Other names

Canonical SPDI

NC_000011.10:116791690:G: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.

0.05571 (C)

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

1000 Genomes Project 0.05571

1000 Genomes Project 30x 0.05887

Trans-Omics for Precision Medicine (TOPMed) 0.06465

Links

ClinGen: CA116845 UniProtKB: Q6Q788#VAR_021165 OMIM: 606368.0002 dbSNP: rs3135506 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.
APOA5		-	-	GRCh38 GRCh37	188	258
LOC108491825	-	-	-	GRCh38	-	50

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.
Hypertriglyceridemia 1	risk factor (1)	no assertion criteria provided	Nov 15, 2002	RCV000004653.5
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV002054414.8
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Feb 11, 2019	RCV002345231.4
not specified	Likely benign (1)	criteria provided, single submitter	Jul 18, 2023	RCV003323351.2
Familial type 5 hyperlipoproteinemia Hypertriglyceridemia 1	Benign (1)	criteria provided, single submitter	Apr 7, 2022	RCV002504745.3

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.
Benign (Apr 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial type 5 hyperlipoproteinemia Hypertriglyceridemia 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002804574.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Jul 18, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029781.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023
Benign (Jan 31, 2024)	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: SCV002438509.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005231737.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Feb 11, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002652493.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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. (less)
risk factor (Nov 15, 2002)	no assertion criteria provided Method: literature only	HYPERTRIGLYCERIDEMIA, SUSCEPTIBILITY TO, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024827.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 08, 2021	Publications: PubMed (2) PubMed: 12417524‚ 12417525 Comment on evidence: Pennacchio et al. (2002) identified an APOA5 haplotype, APOA53, defined by a 56C-G transversion, resulting in a ser19-to-trp (S19W) substitution. The APOA53 haplotype was associated … (more) Pennacchio et al. (2002) identified an APOA5 haplotype, APOA53, defined by a 56C-G transversion, resulting in a ser19-to-trp (S19W) substitution. The APOA53 haplotype was associated with high plasma triglyceride levels (HYTG1; 145750) in 3 independent samples: 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, 419 Caucasian men and women who were studied while consuming their self-selected diets as well as after high-carbohydrate and high-fat diets, and 2,660 randomly selected individuals of various ethnicities. The APOA5*3 haplotype was found in 7% of African Americans, 6% of Caucasians, and 15% of Hispanics. In a cohort of 2,808 healthy middle-aged men, Talmud et al. (2002) reported an association between homozygosity for S19W and elevated triglyceride levels (p = 0.003). (less)

Comment:

This alteration is classified as 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.

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
Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.	Talmud PJ	Human molecular genetics	2002	PMID: 12417525
Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.	Pennacchio LA	Human molecular genetics	2002	PMID: 12417524

Text-mined citations for rs3135506 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001371904.1(APOA5):c.56C>G (p.Ser19Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3135506 ...