Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002375113 | SCV002684775 | uncertain significance | Cardiovascular phenotype | 2024-11-23 | criteria provided, single submitter | clinical testing | The p.S4244C variant (also known as c.12731C>G), located in coding exon 29 of the APOB gene, results from a C to G substitution at nucleotide position 12731. The serine at codon 4244 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002491583 | SCV002777345 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2021-08-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002491583 | SCV003782374 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2025-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 4244 of the APOB protein (p.Ser4244Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (internal data). ClinVar contains an entry for this variant (Variation ID: 928142). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APOB protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| New York Genome Center | RCV002491583 | SCV003925088 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2022-04-22 | criteria provided, single submitter | clinical testing | The c.12731C>G variant in APOB has not previously been reported in the literature, however, it has been deposited in ClinVar as a Variant of Uncertain Significance for familial hypercholesterolemia [ClinVar ID: 928142]. The c.12731C>G variant is observed in 73 alleles (~0.009% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of US), suggesting it is not a common benign variant in the populations represented in those databases. The c.12731C>G variant is located in exon 29 of this 29-exon gene and predicted to replace serine amino acid with cysteine at position 4244 in alpha 3 domain of APOB protein (PMID: 19200547). In silico tools predict the p.(Ser4244Cys) variant to be benign [REVEL = 0.073]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.12731C>G p.(Ser4244Cys) variant identified in APOB is classified as a Variant of Uncertain Significance. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478726 | SCV004221652 | uncertain significance | not provided | 2023-04-24 | criteria provided, single submitter | clinical testing | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34502 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |