Submissions for variant NM_000384.3(APOB):c.288G>T (p.Gln96His)

gnomAD frequency: 0.00012  dbSNP: rs186544754

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094654	SCV000427188	likely benign	Hypercholesterolemia, autosomal dominant, type B	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000344371	SCV000427189	uncertain significance	Familial hypobetalipoproteinemia 1	2018-01-12	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.
GeneDx	RCV000522955	SCV000619075	uncertain significance	not provided	2017-07-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the APOB gene. The Q96H variant has been reported in three Chinese patients referred for coronary angiography and subsequently diagnosed with FH (Li et al., 2017); however, additional clinical information was not provided. This variant is observed in 0.54%-1% alleles from individuals of East Asian background in large population cohorts, which is greater than expected for this disorder (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). This substitution occurs at a position that is not conserved across species and where histidine (H) is present as the wild type in at least one species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the Q96H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837884	SCV000659275	benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2025-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000289349	SCV000687223	likely benign	Hypercholesterolemia, familial, 1	2017-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436197	SCV002750535	likely benign	Cardiovascular phenotype	2020-10-13	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000522955	SCV001977991	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000522955	SCV001979199	likely benign	not provided		no assertion criteria provided	clinical testing