Submissions for variant NM_022437.3(ABCG8):c.628G>A (p.Val210Met)

gnomAD frequency: 0.01336  dbSNP: rs9282574

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000268337	SCV000430511	benign	Sitosterolemia 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000955917	SCV001102654	benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365402	SCV002660944	benign	Cardiovascular phenotype	2019-05-03	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001702429	SCV005075954	likely benign	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: ABCG8 c.628G>A (p.Val210Met) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 0.0036 in 250926 control chromosomes, predominantly at a frequency of 0.048 within the African or African-American subpopulation in the gnomAD database, including 17 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCG8 causing Early Onset Coronary Artery Disease phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.628G>A has been reported in the literature in individual(s) affected with Early Onset Coronary Artery Disease as an Likely Benign change (Reeskamp_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32088153). ClinVar contains an entry for this variant (Variation ID: 336070). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000955917	SCV001917132	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702429	SCV001929141	benign	not specified		no assertion criteria provided	clinical testing