ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.13288T>A (p.Ser4430Thr)

gnomAD frequency: 0.00008  dbSNP: rs72654426
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000455461 SCV000538320 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 paper, no segs
Illumina Laboratory Services, Illumina RCV001141493 SCV001301842 uncertain significance Hypercholesterolemia, autosomal dominant, type B 2019-08-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001141493 SCV001429083 uncertain significance Hypercholesterolemia, autosomal dominant, type B 2018-07-10 criteria provided, single submitter clinical testing
GeneDx RCV001753857 SCV001986133 uncertain significance not provided 2020-10-14 criteria provided, single submitter clinical testing Identified in association with hypertriglyceridemia in the published literature, reported as S4403T due to alternate nomenclature (Johansen et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#402373; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20657596)
Invitae RCV001861655 SCV002170185 likely benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-09-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002379403 SCV002693018 uncertain significance Cardiovascular phenotype 2022-12-08 criteria provided, single submitter clinical testing The p.S4430T variant (also known as c.13288T>A), located in coding exon 29 of the APOB gene, results from a T to A substitution at nucleotide position 13288. The serine at codon 4430 is replaced by threonine, an amino acid with similar properties. This alteration was reported in association with hypertriglyceridemia (Johansen CT et al. Nat. Genet., 2010 Aug;42:684-7; Sjouke B et al. J Clin Lipidol, 2016 Sep;10:1462-1469). This alteration has also been reported in a Turkish whole exome sequencing cohort (Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This amino acid position is poorly conserved in available 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.
Revvity Omics, Revvity Omics RCV001753857 SCV003826865 uncertain significance not provided 2021-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000455461 SCV004099634 likely benign not specified 2023-09-08 criteria provided, single submitter clinical testing Variant summary: APOB c.13288T>A (p.Ser4430Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249878 control chromosomes. The observed variant frequency is approximately 3.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in APOB causing Familial Hypercholesterolemia phenotype (2e-05), strongly suggesting that the variant is benign. c.13288T>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia or hypertriglyceridemia without strong evidence of causality (e.g. Johansen_2010, Kusters_2013, Sjouke_2016). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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