ClinVar Genomic variation as it relates to human health

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.

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant have been previously reported in individuals with high density lipoprotein (HDL) deficiency or abnormal cholesterol levels [PMID 15297675, 20981092, 20880529, 26255038, 24497850]

Variant summary: ABCA1 c.3542C>T (p.Ser1181Phe) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of 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 0.0013 in 251430 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 160- fold 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3542C>T has been reported in the literature in individuals affected with low HDL cholesterol (e.g. Cohen_2004, Candini_2010, Tietjen_2012). However, the variant has also been found at a similar frequency in cases and controls in a study of individuals with early onset myocaridal infarction (e.g. Beaudoin_2012). These reports 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

BS1

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.