Submissions for variant NM_005502.4(ABCA1):c.1196T>C (p.Val399Ala)

gnomAD frequency: 0.00352  dbSNP: rs9282543

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000404525	SCV000476327	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	RCV000300129	SCV000476328	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). 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.
Eurofins Ntd Llc (ga)	RCV000594571	SCV000706252	uncertain significance	not provided	2018-04-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779671	SCV000916391	likely benign	not specified	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: ABCA1 c.1196T>C (p.Val399Ala) results in a non-conservative amino acid change located in the first extracellular loop (Vaughan_2009) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 276532 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 289-folds higher than 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, c.1196T>C has been reported in the literature in individuals affected with Tangier Disease and low HDL-C levels (Abdel-Razek_2018, Bodzioch_1999, Kiss_2007, Sadananda_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Tangier Disease or with Early Onset Coronary Artery Disease. A publication, Vaughan_2009 could have mild implications into ABCA1 function but the association of this with pathophysiology and mechanism of disease is not clearly established. Two ClinVar submissions from clinical diagnostic laboratories (evaluations after 2014) cites the variant with conflicting classifications "VOUS" or "likely benign." In addition, the variant has been indicated to have an association with low HDL-C levels, however, multiple studies, Clee_2001, Saleheen_2007, found no association for the variant. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000594571	SCV001815333	likely benign	not provided	2020-07-16	criteria provided, single submitter	clinical testing	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26255038, 10431237, 24497850, 18776170, 24503134, 22995991, 11238261)
Invitae	RCV000594571	SCV002340186	benign	not provided	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338956	SCV002640607	likely benign	Cardiovascular phenotype	2019-04-12	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.
New York Genome Center	RCV002467767	SCV002764387	uncertain significance	Hypoalphalipoproteinemia, primary, 1; Tangier disease	2021-10-06	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000404525	SCV004812666	likely benign	Tangier disease	2023-10-06	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000779671	SCV001917421	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000779671	SCV001966329	benign	not specified		no assertion criteria provided	clinical testing