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

gnomAD frequency: 0.00250  dbSNP: rs183812948

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837970	SCV000659266	benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2025-01-26	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
GENinCode PLC	RCV004584752	SCV005074050	benign	Familial hypercholesterolemia	2022-06-17	criteria provided, single submitter	clinical testing
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.
PreventionGenetics, part of Exact Sciences	RCV004543254	SCV004760475	likely benign	APOB-related disorder	2020-04-24	no assertion criteria provided	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).