ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.3740A>G (p.Tyr1247Cys) (rs61741164)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000256241 SCV000322842 benign Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 2/96 normolipidaemic Portuguese controls
GeneDx RCV000524085 SCV000620472 uncertain significance not specified 2017-09-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the APOB gene. The Y1247C variant has been reported as a benign variant in one study where it was found in the control population and did not segregate with FH in one family (Alves et al., 2014). This variant is observed in 0.1% alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is not conserved across species. However, the Y1247C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000532315 SCV000659281 likely benign Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2017-08-08 criteria provided, single submitter clinical testing
Color RCV000775214 SCV000909457 uncertain significance Familial hypercholesterolemias 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence (favor benign): This variant (also known as p.Tyr1220Cys in the mature protein) is a missense variant located in the beta1 domain of the APOB protein. Computational prediction tools and conservation analyses are conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional assays measuring LDL binding and internalization did not demonstrate an affect on APOB function (PMID 24234650) and the variant did not segregate with FH in one family (PMID 24234650). This variant has been identified in 29/24032 African chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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