Submissions for variant NM_000033.4(ABCD1):c.565C>T (p.Arg189Trp)

dbSNP: rs1131691916

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493301	SCV000583137	likely pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30069915, 15811009, 31589614, 10737980, 33920672, 35466195, 34649108, 36046390)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633486	SCV000754719	pathogenic	Adrenoleukodystrophy	2024-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the ABCD1 protein (p.Arg189Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ABCD1-related conditions (PMID: 10737980, 15811009, 30069915). ClinVar contains an entry for this variant (Variation ID: 430349). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000493301	SCV001446600	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000493301	SCV002023947	likely pathogenic	not provided	2023-05-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000633486	SCV002045809	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000633486	SCV002059184	likely pathogenic	Adrenoleukodystrophy	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430349, PMID:10737980, PS1_S). A different missense change at the same codon has been reported to be associated with ABCD1 related disorder (PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, 3CNET: 0.986, PP3_P). A missense variant is a common mechanism associated with Adrenomyeloneuropathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002350104	SCV002651867	likely pathogenic	Inborn genetic diseases	2018-04-17	criteria provided, single submitter	clinical testing	The p.R189W variant (also known as c.565C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 565. The arginine at codon 189 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in one individual with Addison disease and one individual with adrenomyeloneuropathy; both individuals had elevated very long chain fatty acid plasma concentrations (Lachtermacher MB et al. Hum. Mutat., 2000;15:348-53; Coll MJ et al. Clin. Genet., 2005 May;67:418-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV000633486	SCV004208196	likely pathogenic	Adrenoleukodystrophy	2023-03-30	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000633486	SCV004814219	likely pathogenic	Adrenoleukodystrophy	2021-01-27	criteria provided, single submitter	clinical testing	Criteria Codes: PS4_Mod PM2 PP3 PP4
Solve-RD Consortium	RCV000633486	SCV005091342	likely pathogenic	Adrenoleukodystrophy	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team