Submissions for variant NM_022436.3(ABCG5):c.1864A>G (p.Met622Val)

gnomAD frequency: 0.00461  dbSNP: rs140374206

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174593	SCV000225915	likely benign	not specified	2016-04-26	criteria provided, single submitter	clinical testing
Invitae	RCV000624964	SCV001101526	benign	Sitosterolemia	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141536	SCV001301889	likely benign	Sitosterolemia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001706120	SCV001908842	benign	not provided	2019-05-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000174593	SCV002070899	benign	not specified	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408758	SCV002724125	benign	Cardiovascular phenotype	2019-08-30	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	RCV002505248	SCV002807978	likely benign	Sitosterolemia 2	2022-02-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001706120	SCV002822632	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ABCG5: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000174593	SCV004122417	likely benign	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: ABCG5 c.1864A>G (p.Met622Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0054 in 250610 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease phenotype (0.005), strongly suggesting that the variant is benign. c.1864A>G has been reported in the literature in individuals affected with sitosterolemia or high cholesterol (e.g., Hubacek_2001, Rees_2005), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore 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 publications have been ascertained in the context of this evaluation (PMID: 11668628, 28748566, 16029460). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001706120	SCV002034090	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706120	SCV002034378	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000174593	SCV002038179	benign	not specified		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001141536	SCV002515688	uncertain significance	Sitosterolemia 1		no assertion criteria provided	research