Submissions for variant NM_000384.3(APOB):c.9491C>T (p.Thr3164Met)

gnomAD frequency: 0.00007  dbSNP: rs143269114

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001027448	SCV000426999	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	RCV000322332	SCV000427000	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850801	SCV002154051	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-11-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001850801	SCV002816338	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2021-10-07	criteria provided, single submitter	clinical testing
GeneDx	RCV002521388	SCV003194971	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Reported among a cohort of individuals with nonalcoholic fatty liver disease and hepatocellular carcinoma (Pelusi et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T3137M); This variant is associated with the following publications: (PMID: 30076208, 30842500)
PreventionGenetics, part of Exact Sciences	RCV004530349	SCV004114629	uncertain significance	APOB-related disorder	2022-08-29	criteria provided, single submitter	clinical testing	The APOB c.9491C>T variant is predicted to result in the amino acid substitution p.Thr3164Met. This variant has been reported in an individual with Hepatocellular carcinoma, in nonalcoholic fatty liver disease (Pelusi et al. 2019. PubMed ID: 30842500. Suppl. data). This variant is reported in 0.050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21230249-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004984834	SCV005475231	benign	Cardiovascular phenotype	2024-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001027448	SCV001190016	likely pathogenic	Familial hypobetalipoproteinemia 1	2018-12-01	flagged submission	case-control