Submissions for variant NM_005502.4(ABCA1):c.254C>T (p.Pro85Leu)

gnomAD frequency: 0.00121  dbSNP: rs145183203

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000288931	SCV000476365	likely benign	Tangier disease	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.
Illumina Laboratory Services, Illumina	RCV000346255	SCV000476366	likely benign	Hypoalphalipoproteinemia, primary, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001490534	SCV001695102	likely benign	not provided	2024-12-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001490534	SCV001716024	uncertain significance	not provided	2021-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282127	SCV002571867	likely benign	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: ABCA1 c.254C>T (p.Pro85Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 258052 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 112.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Early Onset Coronary Artery Disease phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant has been reported in the literature in the heterozygous state only (or unstated), in individuals with low HDL-C, FH, MI and hypoalphalipoproteinemia (Colin_2014, Beaudoin_2012, Luirink_2019, Geller_2018, Dong_2022), and in some tested individuals was associated with lower HDL-C levels (Cohen_2004), without strong evidence for causality. The variant was found in at least 1 pt with critically low HDL and personal history of CAD, however 4 additional family members who carried this variant heterozygously presented only with hypoalphalipoproteinemia but were cardiologically normal (Hong et al.,2002). In at least 1 large scale genome sequencing project, the variant was not associated with HDL-C levels (Morrison_2013) and was reported as 'polymorphism' by Kiss et. al, 2007. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. In addition, cholesterol efflux was found to be higher in cells from an individual with the variant compared to normal controls, while other variants associated with lower HDL-C levels had cholesterol efflux levels less than two standard deviations below the mean in subjects with normal HDL-C (Cohen_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Two submitters have classified the variant as likely benign, while two classified as VUS and one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV001490534	SCV003824294	uncertain significance	not provided	2021-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992191	SCV005561691	likely benign	Cardiovascular phenotype	2024-09-12	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.
Clinical Genetics, Academic Medical Center	RCV001490534	SCV001917253	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001490534	SCV001974833	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732861	SCV005347125	likely benign	ABCA1-related disorder	2024-04-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).