ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.6034C>T (p.Arg2012Ter)

gnomAD frequency: 0.00002  dbSNP: rs147863759
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV003227929 SCV003925339 pathogenic Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2022-04-08 criteria provided, single submitter clinical testing The c.6034C>T (p.Arg2012Ter) variant identified in the APOB gene has been previously reported in the literature in individuals with Hypobetalipoproteinemia (PMID: 8843188, 24507775, 30782561). This variant has three heterozygous in gnomAD v2.1.1 and v3.1.1, and three heterozygous in TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The c.6034C>T variant is located in exon 26 of this 29-exon gene, predicted to incorporate a premature termination codon at position 2012, and result in either haploinsufficiency via nonsense-mediated decay or loss of more than 50% of the wild-type protein if translated. There are multiple downstream truncating variants reported in ClinVar or literature in affected individuals with Hypobetalipoproteinemia. Based on the available evidence this c.6034C>T (p.Arg2012Ter) variant is classified here as Pathogenic.
Invitae RCV003227929 SCV004569689 pathogenic Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2012*) in the APOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APOB are known to be pathogenic (PMID: 20032471). This variant is present in population databases (rs147863759, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal dominant hypobetalipoproteinemia (PMID: 30782561). This variant is also known as ApoB-43.7 or p.Arg1986*. For these reasons, this variant has been classified as Pathogenic.

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