Submissions for variant NM_005502.4(ABCA1):c.5192C>G (p.Ser1731Cys)

gnomAD frequency: 0.00001  dbSNP: rs760507032

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778869	SCV000915266	pathogenic	Hypoalphalipoproteinemia, primary, 1	2018-10-08	criteria provided, single submitter	clinical testing	The ABCA1 c.5192C>G (p.Ser1731Cys) missense variant has been reported in four studies in which it is found in at least 25 individuals from six different French Canadian families affected with familial high density lipoprotein deficiency (Clee et al. 2001; Cohen et al. 2004; Alrasadi et al. 2006; Reddy et al. 2012). Many of the individuals with HDL-C levels in the fifth centile or below from these families were found to carry the p.Ser1731Cys variant. The variant has been reported in the literature almost exclusively in families of French Canadian heritage. The p.Ser1731Cys variant was absent from 387 total individuals from two different Canadian control populations and another 256 individuals in a control population from the Dallas Heart Study and is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. The variant was not fully penetrant, and some families did include affected individuals who did not carry the variant (Alrasadi et al. 2006). In some families, the p.Ser1731Cys variant seems to be capable of causing disease in a dominant fashion with low penetrance on its own, but the pathogenic effect of this variant appears to be most pronounced in the presence of other alleles in other genes (Cohen et al. 2004). Functional studies demonstrated that cells transfected with the p.Ser1731Cys allele displayed a significant reduction in cholesterol efflux relative to wildtype ABCA1 (P<0.01), indicating that this variant significantly impairs ABCA1 function (Brunham et al., 2005). Based on the evidence, the p.Ser1731Cys variant is classified as pathogenic for familial high density lipoprotein deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001166176	SCV001328517	uncertain significance	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330947	SCV004038428	uncertain significance	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: ABCA1 c.5192C>G (p.Ser1731Cys) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250852 control chromosomes (gnomAD). c.5192C>G has been reported in the literature in multiple individuals with Familial Hypoalphalipoproteinemia (e.g. Cohen_2004, Alrasadi_2006, Reddy_2012), predominately from several French Canadian families; however in these families the variant is observed with low penetrance and in cases where other variant(s) are suspected to be involved in the manifestation of the phenotype (Alrasadi_2006, Reddy_2012). As a result, no conclusions indicating a strong penetrant association of the variant with Familial Hypoalphalipoproteinemia can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found the variant results in impaired cholesterol efflux, approximately 30-50% compared to that of the WT protein (Kiss_2007). The following publications have been ascertained in the context of this evaluation (PMID: 16343503, 11238261, 15297675, 32041611, 17303779, 22923419). There have been two clinical-significance assessments submitted for this variant to ClinVar after 2014. One classified the variant as pathogenic and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.