Submissions for variant NM_000384.3(APOB):c.1061A>G (p.Glu354Gly)

gnomAD frequency: 0.00004  dbSNP: rs149227065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094644	SCV000427164	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	RCV000261155	SCV000427165	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.
Robarts Research Institute, Western University	RCV000388409	SCV000782790	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985329	SCV001133384	uncertain significance	not provided	2019-06-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411228	SCV002716910	uncertain significance	Cardiovascular phenotype	2021-09-26	criteria provided, single submitter	clinical testing	The p.E354G variant (also known as c.1061A>G), located in coding exon 9 of the APOB gene, results from an A to G substitution at nucleotide position 1061. The glutamic acid at codon 354 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002521389	SCV002967614	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-12-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530356	SCV004113443	uncertain significance	APOB-related disorder	2022-10-31	criteria provided, single submitter	clinical testing	The APOB c.1061A>G variant is predicted to result in the amino acid substitution p.Glu354Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-21256234-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993933	SCV004813569	uncertain significance	not specified	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: APOB c.1061A>G (p.Glu354Gly) results in a non-conservative amino acid change located in the Vitellogenin, N-terminal domain (IPR001747) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251442 control chromosomes (gnomAD). The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOB causing Early Onset Coronary Artery Disease phenotype (2e-05). To our knowledge, no occurrence of c.1061A>G in individuals affected with Early Onset Coronary Artery Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 334175). Based on the evidence outlined above, the variant was classified as uncertain significance.