ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.2938G>A (p.Ala980Thr)

gnomAD frequency: 0.00007  dbSNP: rs369310292
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001837975 SCV000659277 likely benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-10-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV002438504 SCV002747809 uncertain significance Cardiovascular phenotype 2022-10-13 criteria provided, single submitter clinical testing The p.A980T variant (also known as c.2938G>A), located in coding exon 19 of the APOB gene, results from a G to A substitution at nucleotide position 2938. The alanine at codon 980 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort (Futema M et al. J. Med. Genet., 2012 Oct;49:644-9). This amino acid position is not well 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.
New York Genome Center RCV001837975 SCV002764364 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-09-17 criteria provided, single submitter clinical testing The c.2938G>A (p.Ala980Thr) variant identified in the APOB gene substitutes a moderately conserved Alanine for Threonine at amino acid 980/4564 (exon 19/29). This variant is found with low frequency in gnomAD(v3.1.1) (10 heterozygotes, 0 homozygotes; allele frequency: 6.57e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.492) and Benign (REVEL; score:0.054) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:477805), and has been identified in a single individual in the literature with Familial Hypercholesterolemia [PMID:23054246]. The p.Ala980 residue is not within a mapped domain of APOB (UniProtKB:P04114). Given the lack of compelling evidence for its pathogenicity, the c.2938G>A (p.Ala980Thr) variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
GeneDx RCV003319380 SCV004024050 uncertain significance not provided 2023-02-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23054246)
PreventionGenetics, part of Exact Sciences RCV004530588 SCV004712159 uncertain significance APOB-related disorder 2024-02-08 criteria provided, single submitter clinical testing The APOB c.2938G>A variant is predicted to result in the amino acid substitution p.Ala980Thr. This variant has been reported in an individual with familial hypercholesterolemia (Futema et al. 2012. PubMed ID: 23054246. Table S1). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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