NM_000384.3(APOB):c.2981C>T (p.Pro994Leu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Apr 25, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000766983.44

Allele description [Variation Report for NM_000384.3(APOB):c.2981C>T (p.Pro994Leu)]

NM_000384.3(APOB):c.2981C>T (p.Pro994Leu)

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.2981C>T (p.Pro994Leu)

HGVS:

NC_000002.12:g.21019741G>A
NG_011793.1:g.29333C>T
NM_000384.3:c.2981C>TMANE SELECT
NP_000375.3:p.Pro994Leu
NC_000002.11:g.21242613G>A
NM_000384.2:c.2981C>T

Protein change:

P994L

Links:

Molecular consequence:

NM_000384.3:c.2981C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Mus musculus CDKN1A interacting zinc finger protein 1 (Ciz1), transcr...
PREDICTED: Mus musculus CDKN1A interacting zinc finger protein 1 (Ciz1), transcript variant X26, mRNA
gi|1907143089|ref|XM_036162521.1|

Nucleotide
PREDICTED: Mus musculus CDKN1A interacting zinc finger protein 1 (Ciz1), transcr...
PREDICTED: Mus musculus CDKN1A interacting zinc finger protein 1 (Ciz1), transcript variant X18, mRNA
gi|1907143079|ref|XM_006498283.5|

Nucleotide
cip1-interacting zinc finger protein isoform X10 [Mus musculus]
cip1-interacting zinc finger protein isoform X10 [Mus musculus]
gi|1720400471|ref|XP_030107878.1|

Protein
Mus musculus GIT ArfGAP 2 (Git2), transcript variant 12, mRNA
Mus musculus GIT ArfGAP 2 (Git2), transcript variant 12, mRNA
gi|2711571343|ref|NM_001429065.1|

Nucleotide
UI-M-BH1-alh-a-04-0-UI.s1 NIH_BMAP_M_S2 Mus musculus cDNA clone UI-M-BH1-alh-a-0...
UI-M-BH1-alh-a-04-0-UI.s1 NIH_BMAP_M_S2 Mus musculus cDNA clone UI-M-BH1-alh-a-04-0-UI 3', mRNA sequence
gi|5905704|gnl|dbEST|3175829|gb|AW0 .1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617639	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 25, 2024)	germline	clinical testing	Citation Link,
SCV000924754	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Feb 9, 2017)	germline	provider interpretation
SCV001133402	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Jun 30, 2022)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30694319, 33303402, 30270084, 24234650, 22095935, 26467025
SCV002063834	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV002506115	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Oct 2, 2023)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	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, provider interpretation
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.

Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Di Angelantonio E, Danesh J, Nicholls SJ, Bhatt DL, Sabatine MS, Catapano AL.

JAMA. 2019 Jan 29;321(4):364-373. doi: 10.1001/jama.2018.20045.

PubMed [citation]

PMID:: 30694319
PMCID:: PMC6439767

Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.

Gill PK, Dron JS, Berberich AJ, Wang J, McIntyre AD, Cao H, Hegele RA.

J Clin Lipidol. 2021 Jan-Feb;15(1):79-87. doi: 10.1016/j.jacl.2020.11.006. Epub 2020 Nov 24.

PubMed [citation]

PMID:: 33303402

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000617639.5

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

Description

Reported in patients with hypercholesterolemia and combined hyperlipidemia; however, some patients also harbored additional variants in hypercholesterolemia-related genes (PMID: 24234650, 22095935, 29459468, 33303402, 34456049); In vitro functional studies in LDL separated from lymphocytes and U937 cells showed the APOB-P994L had a neutral effect on LDL-binding and proliferation (PMID: 30270084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22095935, 37937776, 22534770, 30270084, 33303402, 29459468, 34456049, 35913489, 24234650, 37848354, 36190978, Malaquias2023 [abstract], 30694319)

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924754.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Genetic testing: The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. p.Pro994Leu (c.2981C>T) in the APOB gene (NM_000384.2) The lab classifies this variant as a variant of unknown significance. Given a lack of significant case data and presence in the general population we consider this variant of unknown significance, likely benign and we do not feel it is related to a patient's condition and is not suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was reported by Alves AC et al. Hum Mol Genet. 2014;23(7):1817-28 in a patient with FH that also had a pathogenic LDLR variant, otherwise it has not been reported in patients with FH. Invitae Genetics has seen this variant and reported it as likely benign in Clinvar. Our patient has heterozygous FH and a very likely pathogenic variant in LDLR making it even less likely that this causes FH. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar: 0.411). The proline at codon 994 is conserved across species with the exception of the mega bat. There are no pathogenic variants listed in clinvar near codon 994. There are 140 individuals with variation at codon 994 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 141,246 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. This corresponds to a frequency of 1 in 1009 individuals and is too common to be a significant cause of FH given it's lack of presence in patients with FH.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001133402.5

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

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV002063834.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

APOB: BP4

#	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		3	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002506115.3

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

#	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: Nov 3, 2024

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