Submissions for variant NM_000384.3(APOB):c.11401T>A (p.Ser3801Thr)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001837766	SCV000284756	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-01-29	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256297	SCV000322858	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000256297	SCV000588456	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000256297	SCV000687193	uncertain significance	Hypercholesterolemia, familial, 1	2017-07-10	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Ser3774Thr in the mature protein) is a missense variant located in the beta 2 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with FH in the literature. This variant has been identified in 323/277014 chromosomes (238/126528 European chromosomes) with 1 homozygote in the general population by the Genome Aggregation Database (gnomAD). Although this variant is fairly common in the population (0.12%), evidence is insufficient to rule out its pathogenicity conclusively.
GeneDx	RCV000229662	SCV000725343	likely benign	not provided	2020-11-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30270084)
Iberoamerican FH Network	RCV000256297	SCV000748109	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000256297	SCV000782795	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000229662	SCV001156208	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	APOB: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001143642	SCV001304183	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	RCV001143643	SCV001304184	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	RCV000256297	SCV001433277	uncertain significance	Hypercholesterolemia, familial, 1	2019-10-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000229662	SCV001470679	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450668	SCV002612616	likely benign	Cardiovascular phenotype	2018-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000229662	SCV004562245	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	The APOB c.11401T>A; p.Ser3801Thr variant (rs12713540) is reported in the literature in at least one individual with familial hypercholesterolemia (Alves 2018, Medeiros 2016), and in an individual with severe proliferative diabetic retinopathy (Ung 2017). This variant is also reported in ClinVar (Variation ID: 237734). It is found in the general population with an overall allele frequency of 0.1% (333/282686 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.102). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Alves AC et al. Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia. Atherosclerosis. 2018 Oct;277:448-456. PMID: 30270084. Medeiros AM et al. Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. Genet Med. 2016 Apr;18(4):316-24. PMID: 26020417. Ung C et al. Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Res. 2017 Oct;139:168-176. PMID: 28431867.
PreventionGenetics, part of Exact Sciences	RCV003919919	SCV004733569	likely benign	APOB-related condition	2022-07-18	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).
Clinical Genetics, Academic Medical Center	RCV000603743	SCV001918325	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000229662	SCV001974409	likely benign	not provided		no assertion criteria provided	clinical testing