ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.13369G>A (p.Asp4457Asn)

gnomAD frequency: 0.00250  dbSNP: rs183812948
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001837970 SCV000659266 benign Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2024-01-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001138900 SCV001298991 uncertain significance Hypercholesterolemia, autosomal dominant, type B 2018-01-13 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 RCV001138901 SCV001298992 uncertain significance Familial hypobetalipoproteinemia 1 2018-01-13 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256751 SCV001433160 benign not specified 2020-01-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001283873 SCV001469331 likely benign not provided 2020-07-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV002384270 SCV002690368 likely benign Cardiovascular phenotype 2016-11-02 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.
CeGaT Center for Human Genetics Tuebingen RCV001283873 SCV002822615 likely benign not provided 2022-10-01 criteria provided, single submitter clinical testing APOB: BP4, BS2
PreventionGenetics, part of Exact Sciences RCV004543254 SCV004760475 likely benign APOB-related disorder 2020-04-24 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001283873 SCV001551514 likely benign not provided no assertion criteria provided clinical testing The APOB p.D4457N variant was not identified in the literature but was identified in dbSNP (ID: rs183812948) and ClinVar (classified as uncertain significance by Illumina, as likely benign by Color, and as benign by Invitae). The variant was identified in control databases in 199 of 281656 chromosomes (4 homozygous) at a frequency of 0.0007065, and was observed at the highest frequency in the Latino population in 176 of 35374 chromosomes (freq: 0.004975) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.D4457 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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