Submissions for variant NM_022437.3(ABCG8):c.55G>C (p.Asp19His)

gnomAD frequency: 0.06566  dbSNP: rs11887534

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000266053	SCV000340356	benign	not specified	2016-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000269126	SCV000430500	likely benign	Sitosterolemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094725	SCV000483933	benign	Sitosterolemia 1	2018-03-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001705581	SCV000949102	association	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the ABCG8 protein (p.Asp19His). This variant is present in population databases (rs11887534, gnomAD 10%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies have shown that this variant is associated with reduced serum phytosterol levels and confers susceptibility to gallstone disease (PMID: 11893785, 17632509, 21039838, 21274884, 22898925). In a large meta-analysis with 4,381 cases and 3,765 controls (PMID: 22898925), individuals carrying this variant had an increased overall risk of gallstone disease (2.07, 95% CI: 1.65-2.60). ClinVar contains an entry for this variant (Variation ID: 4975). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense causes a gain of ABCG8 protein function in vitro, contrary to the loss of ABCG8 protein function associated with sitosterolemia (PMID: 22898925). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.
Mendelics	RCV000269126	SCV001135671	benign	Sitosterolemia	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001705581	SCV001841286	benign	not provided	2018-07-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29764733, 31327807, 30975109, 30036524, 11893785, 17632509, 20581104, 21039838, 22898925, 20163776, 20592455, 22675952, 20170916)
Ambry Genetics	RCV002345232	SCV002648864	benign	Cardiovascular phenotype	2018-12-03	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.
Fulgent Genetics, Fulgent Genetics	RCV002490320	SCV002796617	likely benign	Sitosterolemia 2	2021-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000266053	SCV004029676	likely benign	not specified	2023-07-17	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001705581	SCV005240549	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000005263	SCV000025441	pathogenic	Gallbladder disease 4	2007-08-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000266053	SCV001918137	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000266053	SCV001929981	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003982825	SCV004799801	benign	ABCG8-related disorder	2023-11-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).