Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000550830 | SCV000659277 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 | 2018-04-18 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 980 of the APOB protein (p.Ala980Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs369310292, ExAC 0.02%). This variant has been reported in the literature in an individual affected with hypercholesterolemia (PMID: 23054246). ClinVar contains an entry for this variant (Variation ID: 477805). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Color | RCV000775551 | SCV000909915 | uncertain significance | Familial hypercholesterolemias | 2018-05-01 | criteria provided, single submitter | clinical testing | Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Ala953Thr in the mature protein) is a missense variant located in the BetaAlpha1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact 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. This variant has been reported in one individual affected with familial hypercholesterolemia in the literature (PMID 23054246). This variant is rare in the general population and has been identified in 16/277162 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. |