ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.1205A>G (p.His402Arg)

dbSNP: rs965602697
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002026706 SCV002316681 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-11-26 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 402 of the APOB protein (p.His402Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with APOB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002346305 SCV002648862 uncertain significance Cardiovascular phenotype 2022-07-03 criteria provided, single submitter clinical testing The p.H402R variant (also known as c.1205A>G), located in coding exon 10 of the APOB gene, results from an A to G substitution at nucleotide position 1205. The histidine at codon 402 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. 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 RCV002026706 SCV004046454 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2023-01-23 criteria provided, single submitter clinical testing The c.1205A>G p.(His402Arg) missense variant identified in the APOB gene has previously been deposited in ClinVar as a variant of uncertain significance [ClinVar ID: 1516584] and to our current knowledge has not been reported in an affected individual in the literature. The c.1205A>G variant isobserved in 3 alleles (~0.0007 % minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1205A>G variant is located in exon 10 of this 29-exon gene, and predicted to replace a moderately conserved histidine amino acid with arginine at position 402 of the encoded protein. In silico algorithms do not predict a damaging effect to the function of the canonical protein (REVEL=0.103); however, there are no functional studies to support or refute these predictions. Based on available evidence the c.1205A>G p.(His402Arg) variant identified in APOB is classified as a Variant of Uncertain Significance.

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