NM_000384.3(APOB):c.12739C>T (p.Gln4247Ter) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 12, 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:: RCV001838023.12

Allele description [Variation Report for NM_000384.3(APOB):c.12739C>T (p.Gln4247Ter)]

NM_000384.3(APOB):c.12739C>T (p.Gln4247Ter)

Gene:

APOB:apolipoprotein B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p24.1

Genomic location:

Preferred name:

NM_000384.3(APOB):c.12739C>T (p.Gln4247Ter)

HGVS:

NC_000002.12:g.21002683G>A
NG_011793.1:g.46391C>T
NM_000384.3:c.12739C>TMANE SELECT
NP_000375.3:p.Gln4247Ter
NC_000002.11:g.21225555G>A
NM_000384.2:c.12739C>T

Protein change:

Q4247*

Links:

dbSNP: rs907126709

NCBI 1000 Genomes Browser:

rs907126709

Molecular consequence:

NM_000384.3:c.12739C>T - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000777020	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33418990, 28492532
SCV002776010	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777020

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 12, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002776010

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 12, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.

Meshkov A, Ershova A, Kiseleva A, Zotova E, Sotnikova E, Petukhova A, Zharikova A, Malyshev P, Rozhkova T, Blokhina A, Limonova A, Ramensky V, Divashuk M, Khasanova Z, Bukaeva A, Kurilova O, Skirko O, Pokrovskaya M, Mikova V, Snigir E, Akinshina A, Mitrofanov S, et al.

Genes (Basel). 2021 Jan 6;12(1). doi:pii: 66. 10.3390/genes12010066.

PubMed [citation]

PMID:: 33418990
PMCID:: PMC7825309

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000777020.4

#	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.Gln4247*) in the APOB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 317 amino acid(s) of the APOB protein. This variant is present in population databases (no rsID available, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 33418990). ClinVar contains an entry for this variant (Variation ID: 544074). This variant disrupts a region of the APOB protein in which other variant(s) (p.Tyr4380*) have been observed in individuals with APOB-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

From Fulgent Genetics, Fulgent Genetics, SCV002776010.1

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

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

Last Updated: Oct 8, 2024

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