Submissions for variant NM_005502.4(ABCA1):c.1635C>T (p.Ser545=)

gnomAD frequency: 0.00886  dbSNP: rs9282539

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000387205	SCV000476321	benign	Hypoalphalipoproteinemia, primary, 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.
Illumina Laboratory Services, Illumina	RCV000292762	SCV000476322	benign	Tangier disease	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779666	SCV000916386	benign	not specified	2017-10-23	criteria provided, single submitter	clinical testing	Variant summary: The ABCA1 c.1635C>T (p.Ser545Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts no effect on ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 737/277230 control chromosomes at a frequency of 0.0026584, which is approximately 213 times the estimated maximal expected allele frequency of a pathogenic ABCA1 variant (0.0000125), suggesting this variant is likely a benign polymorphism. In addition, one other clinical diagnostic laboratory classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Invitae	RCV001509631	SCV001716456	benign	not provided	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001509631	SCV001982262	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392921	SCV002703011	likely benign	Cardiovascular phenotype	2019-09-28	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.
PreventionGenetics, part of Exact Sciences	RCV004544706	SCV004785016	benign	ABCA1-related disorder	2024-01-08	criteria provided, single submitter	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).