ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.13444A>G (p.Ile4482Val)

gnomAD frequency: 0.00019  dbSNP: rs142702699
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000263137 SCV000426893 uncertain significance Hypercholesterolemia, autosomal dominant, type B 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000329926 SCV000426894 uncertain significance Familial hypobetalipoproteinemia 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001837828 SCV001412115 likely benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2024-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000997041 SCV002538709 uncertain significance not provided 2022-06-13 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002379223 SCV002688779 likely benign Cardiovascular phenotype 2022-08-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center RCV001837828 SCV002764269 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-03-21 criteria provided, single submitter clinical testing The c.13444A>G (p.Ile4482Val) variant identified in the APOB gene substitutes a poorly conserved Isoleucine for Valine at amino acid 4482/4564 (exon 29/29). This variant is found with an allele frequency of 1.77e-4 (27 heterozygotes, 0 homozygotes) in gnomAD(v3.1.1). In silico algorithms predict this variant to be Tolerated (SIFT; score:1.0) and Benign (REVEL; score: 0.0149) to the function of the canonical transcript. This variant is reported by multiple independent labs in ClinVar as a Variant of Uncertain Significance (VarID:334069) and has been identified in one individual in the literature who was diagnosed with Autosomal Dominant Hypercholesterolemia [PMID:22095935]. The p.Ile4482 residue is not within a mapped domain of APOB (UniProtKB:P04114). Given the lack of compelling evidence for its pathogenicity, the c.13444A>G (p.Ile4482Val) variant identified in the APOB gene is reported as a Variant of Uncertain Significance.
Clinical Genetics, Academic Medical Center RCV000997041 SCV001918469 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000997041 SCV001974087 likely benign not provided no assertion criteria provided clinical testing

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