NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000428946.8

Allele description [Variation Report for NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)]

NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)

Gene:

APOA5:apolipoprotein A5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)

HGVS:

NC_000011.10:g.116790940G>A
NG_015894.2:g.6481C>T
NM_001166598.2:c.289C>T
NM_001371904.1:c.289C>TMANE SELECT
NM_052968.5:c.289C>T
NP_001160070.1:p.Gln97Ter
NP_001358833.1:p.Gln97Ter
NP_443200.2:p.Gln97Ter
NP_443200.2:p.Gln97Ter
NC_000011.9:g.116661656G>A
NG_015894.1:g.6481C>T
NM_052968.4(APOA5):c.289C>T
NM_052968.4:c.289C>T
NM_052968.5:c.289C>T
p.Gln97Ter

Protein change:

Q97*

Links:

dbSNP: rs201079485

NCBI 1000 Genomes Browser:

rs201079485

Molecular consequence:

NM_001166598.2:c.289C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371904.1:c.289C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_052968.5:c.289C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000521319	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 29, 2020)	germline	clinical testing	Citation Link,
SCV001581533	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18324930, 19447388, 23151256, 23307945, 24591733, 28492532
SCV002501779	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18324930, 19447388, 24793350, 25487149, 32041611, 23151256, 27108409, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000521319

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 29, 2020)

germline

clinical testing

Citation Link,

SCV001581533

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002501779

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 17, 2022)

germline

clinical testing

PubMed (8)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia.

Mendoza-Barberá E, Julve J, Nilsson SK, Lookene A, Martín-Campos JM, Roig R, Lechuga-Sancho AM, Sloan JH, Fuentes-Prior P, Blanco-Vaca F.

J Lipid Res. 2013 Mar;54(3):649-661. doi: 10.1194/jlr.M031195. Epub 2013 Jan 10.

PubMed [citation]

PMID:: 23307945
PMCID:: PMC3617940

Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia.

Hooper AJ, Kurtkoti J, Hamilton-Craig I, Burnett JR.

Ann Clin Biochem. 2014 Jul;51(Pt 4):485-9. doi: 10.1177/0004563214525767. Epub 2014 Mar 3.

PubMed [citation]

PMID:: 24591733

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000521319.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 270 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (Stenson et al., 2014); Published functional studies suggest a damaging effect (LPL activity reduced by 90%, mutant protein not detected by Western blot suggesting a null allele, Charrire et al., 2009); This variant is associated with the following publications: (PMID: 24793350, 18324930, 19447388, 23151256, 25487149, 27108409, 28951076, 32041611)

#	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		not provided	not provided	not provided	not provided

From Invitae, SCV001581533.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Gln97*) in the APOA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 270 amino acid(s) of the APOA5 protein. This variant is present in population databases (rs201079485, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal dominant and recessive severe hypertriglyceridemia (PMID: 18324930, 19447388, 23151256, 23307945, 24591733). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381733). For these reasons, this variant has been classified as Pathogenic.

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

From AiLife Diagnostics, AiLife Diagnostics, SCV002501779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

#	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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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