ClinVar Genomic variation as it relates to human health

0/192 non-FH alleles

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

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)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The c.2981C>T (p.Pro994Leu) variant identified in the APOB gene substitutes a well conserved Proline for Leucine at amino acid 994/4564 (exon19/29). This variant is found in gnomAD(v3.1.1) (88 heterozygotes, 0 homozygotes; allele frequency: 5.78e-4). In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Benign (REVEL; score:0.268) to the function of the canonical transcript. This variant is reported in ClinVar as both Likely Benign(n=3) and as aVariant of Uncertain Significance(n=8) (VarID:237743). The c.2981C>T (p.Pro994Leu) variant has been reported in several individuals in the literature [PMID:24234650, 30270084] although in one individual a presumed pathogenic variant in the LDLR gene was also identified, leaving the significance of the APOB variant uncertain. Functional studies in lymphocytes from an affected individual suggest that the p.Pro994Leu variant does not alter LDL-binding capacity, and cell proliferation using a U937 cell proliferation assay was similar to wildtype, although additional functional studies are needed to confirm this finding [PMID:30270084]. The p.Pro994 residue is not within a mapped domain of APOB (UniProtKB:P04114). Given the uncertainty regarding the pathogenicity of the c.2981C>T (p.Pro994Leu) variant identified in the APOB gene, it is reported as a Variant of Uncertain Significance

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

APOB: BP4

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.