ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.13175G>A (p.Ser4392Asn) (rs777718986)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414515 SCV000492192 uncertain significance not specified 2016-12-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the APOB gene. The S4392N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S4392N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, the S4392N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. Lastly, the majority of in silico analyses (2 out of 3) predict this variant likely does not alter the protein structure/function.
GenomeConnect, ClinGen RCV000690044 SCV000840220 not provided Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000690044 SCV000817721 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2018-01-11 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 4392 of the APOB protein (p.Ser4392Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs777718986, ExAC 0.009%). This variant has not been reported in the literature in individuals with APOB-related disease. ClinVar contains an entry for this variant (Variation ID: 373587). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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 and their clinical significance is uncertain. 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.

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