Submissions for variant NM_000384.3(APOB):c.3740A>G (p.Tyr1247Cys)

gnomAD frequency: 0.00071  dbSNP: rs61741164

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256241	SCV000322842	benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	2/96 normolipidaemic Portuguese controls
GeneDx	RCV000532315	SCV000620472	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	Identified in patients with hypercholesterolemia in the published literature; however, this variant did not segregate with disease in an affected relative, was identified in two normolipidaemic control individuals, and functional assays of patient lymphocytes showed no effect on apoB function (PMID: 24234650, 30842500); Identified in one individual with suspected primary hypobetalipoproteinemia (HBL) in the published literature (PMID: 30782561); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y1220C); This variant is associated with the following publications: (PMID: 26020417, 30842500, 35047021, 24234650, 30782561)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837813	SCV000659281	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2025-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001027453	SCV001301148	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.
Illumina Laboratory Services, Illumina	RCV001140852	SCV001301149	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.
Ambry Genetics	RCV002365272	SCV002625717	likely benign	Cardiovascular phenotype	2023-06-05	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.
Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan	RCV001027453	SCV001190021	likely pathogenic	Familial hypobetalipoproteinemia 1	2018-12-01	no assertion criteria provided	case-control
Clinical Genetics, Academic Medical Center	RCV000532315	SCV001921559	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000532315	SCV001969640	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535240	SCV004720062	likely benign	APOB-related disorder	2019-11-08	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).