ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10270T>C (p.Ser3424Pro)

gnomAD frequency: 0.00001  dbSNP: rs1425159052
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001838503 SCV001546619 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-03-07 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1047390). This missense change has been observed in individuals with clinical features of autosomal dominant familial hypercholesterolemia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3424 of the APOB protein (p.Ser3424Pro). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. 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 RCV001838503 SCV002764444 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-11-17 criteria provided, single submitter clinical testing The heterozygous c.10270T>C (p.Ser3424Pro) missense variant identified in the APOB gene has not been reported in affected individuals in the literature. The variant has 0.000006572 allele frequency in the gnomAD(v3) database (1 out of 152172 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported as a Variant of Uncertain Significance in the ClinVar database (Variation ID: 1047390). The variant affects a moderately conserved residue (Ser3424) located in the β2 domain of APOB protein (PMID: 11518754) and is predicted deleterious by multiple in silico prediction tools (CADD score = 24.0, REVEL score = 0.714). Based on the available evidence, the heterozygous c.10270T>C(p.Ser3424Pro) missense variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV001838503 SCV002776774 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-07-09 criteria provided, single submitter clinical testing

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