ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.2981C>T (p.Pro994Leu) (rs41288783)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000766983 SCV000284766 likely benign not provided 2019-02-27 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000256285 SCV000322838 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/192 non-FH alleles
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454922 SCV000538328 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Limited evidence, ExAC: 0.1% (43/66512) European chromosomes
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000256285 SCV000588425 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000766983 SCV000617639 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing The P994L variant of uncertain significance in the APOB gene has been reported in a proband with hypercholesterolemia who also harbors a missense variant in the LDLR gene; both of these variants were present in an affected relative (Alves et al., 2014). Huijgen et al. (2012) also reported this variant in a Dutch patient with autosomal dominant FH. This variant is observed in 134/277040 (0.05%) alleles from individuals of multiple ethnic backgrounds in large population cohorts, indicating that it may be a rare benign variant in this population (Lek et al., 2016). Nevertheless, the P994L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Robarts Research Institute,Western University RCV000256285 SCV000782834 likely benign Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000776116 SCV000910990 uncertain significance Familial hypercholesterolemia 2018-07-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as Pro967Leu in the mature protein) is a missense variant located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is fairly common in the general population and has been identified in 117/126624 non-Finnish European chromosomes (0.0923%) by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766983 SCV001133402 uncertain significance not provided 2019-06-14 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000766983 SCV000924754 uncertain significance not provided 2017-02-09 no assertion criteria provided provider interpretation 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 Ms. Valencia'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;, 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.

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