NM_000384.3(APOB):c.13028_13029del (p.Tyr4343fs) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 21, 2022
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:: RCV002467842.5

Allele description [Variation Report for NM_000384.3(APOB):c.13028_13029del (p.Tyr4343fs)]

NM_000384.3(APOB):c.13028_13029del (p.Tyr4343fs)

Gene:

APOB:apolipoprotein B [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

2p24.1

Genomic location:

Preferred name:

NM_000384.3(APOB):c.13028_13029del (p.Tyr4343fs)

HGVS:

NC_000002.11:g.21225267_21225268del
NC_000002.12:g.21002393AT[1]
NG_011793.1:g.46678AT[1]
NM_000384.3:c.13028_13029delMANE SELECT
NP_000375.3:p.Tyr4343fs
NC_000002.11:g.21225265AT[1]
NC_000002.11:g.21225265_21225266del
NC_000002.11:g.21225267_21225268del
NM_000384.2:c.13028_13029delAT
NM_000384.3:c.13028_13029delATMANE SELECT

Protein change:

Y4343fs

Links:

dbSNP: rs760832994

NCBI 1000 Genomes Browser:

rs760832994

Molecular consequence:

NM_000384.3:c.13028_13029del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hypercholesterolemia, autosomal dominant, type B (FHCL2)
Synonyms:: APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE; APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE; HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007751; MedGen: C1704417; OMIM: 144010

Name:: Familial hypobetalipoproteinemia 1
Synonyms:: Hypobetalipoproteinemia, normotriglyceridemic; Acanthocytosis with hypobetalipoproteinemia
Identifiers:: MONDO: MONDO:0014252; MedGen: C4551990; OMIM: 615558

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Homo sapiens thyroid stimulating hormone, beta (TSHB), mRNA
Homo sapiens thyroid stimulating hormone, beta (TSHB), mRNA
gi|42490754|ref|NM_000549.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002764567	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jan 25, 2021)	germline	clinical testing	Citation Link,
SCV003305305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23775634, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002764567

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(Jan 25, 2021)

germline

clinical testing

Citation Link,

SCV003305305

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 21, 2022)

germline

clinical testing

PubMed (2)
[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	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Molecular description of familial defective APOB-100 in Malaysia.

Al-Khateeb AR, Mohd MS, Yusof Z, Zilfalil BA.

Biochem Genet. 2013 Oct;51(9-10):811-23. doi: 10.1007/s10528-013-9609-6. Epub 2013 Jun 18.

PubMed [citation]

PMID:: 23775634

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From New York Genome Center, SCV002764567.1

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

Description

The c.13028_13029del, p.Tyr4343CysfsTer3 variant identified in the APOB gene has been reported in an individual affected with a mild hypercholesterolemia [PMID:23775634]. This variant causing a frameshift at codon 4343 and a premature translational stop signal three amino acids downstream and the mutant mRNA may escape nonsense-mediated decay and may be expressed as a truncated protein that lacks the last 238 amino acids from the C-terminal end. This variant is found with low frequency in gnomAD v3.1 (1 heterozygotes, 0 homozygotes; allele frequency: 0.0006%) suggesting it is not a common benign variant in the populations represented in that database. Based on available evidence the c.13028_13029del, p.Tyr4343CysfsTer3 variant identified in the APOB gene is reported as a Variant of uncertain significance.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003305305.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Tyr4343Cysfs*3) in the APOB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 221 amino acid(s) of the APOB protein. This variant is present in population databases (rs760832994, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 23775634). ClinVar contains an entry for this variant (Variation ID: 440513). 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.

#	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

Last Updated: Oct 26, 2024

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