ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10700C>T (p.Thr3567Met)

gnomAD frequency: 0.00009  dbSNP: rs368278927
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001837943 SCV001202004 benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-11-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001837943 SCV002781101 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-12-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478083 SCV004220726 uncertain significance not provided 2023-08-29 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals and families affected by hypercholesterolemia (PMIDs: 17964958 (2007), 18325181 (2008), 23775634 (2013), 34428338 (2021)) as well as cardiac disease (PMIDs: 34573395 (2021), 35979295 (2022)). The frequency of this variant in the general population, 0.00015 (3/19940 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488644 SCV004241703 uncertain significance not specified 2023-12-27 criteria provided, single submitter clinical testing Variant summary: APOB c.10700C>T (p.Thr3567Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 1613840 control chromosomes in the gnomAD database (v4.0.0), including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in APOB causing Familial Hypercholesterolemia (5.4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.10700C>T has been reported in the literature in many individuals affected with Familial Hypercholesterolemia (e.g., Yang_2007, Liyanage_2008, Kusters_2013, Elfatih_2021, Yang_2022, Ibrahim_2023), and the variant was said to segregate with disease in at least one family although no data was provided (e.g., Yang_2007). The variant was also reported in at least one individual affected with Tetralogy of Fallot (Pan_2022) as well as one control individual (Johansen_2010). These reports therefore do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Additionally, a co-occurrence with another pathogenic variant was reported in a mother and son affected with Familial Hypercholesterolemia (LDLR c.1448G>A, p.W483X; Yang_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34428338, 20657596, 23833242, 18325181, 36071769, 17964958, 35979295, 37675602). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV004023444 SCV004906204 uncertain significance Cardiovascular phenotype 2023-12-05 criteria provided, single submitter clinical testing Unlikely to be causative of APOB-related hypobetalipoproteinemia (AR) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508852 SCV000605961 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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