Submissions for variant NM_000033.4(ABCD1):c.1978C>T (p.Arg660Trp)

dbSNP: rs1569541203

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000710056	SCV000840438	pathogenic	Adrenoleukodystrophy	2017-10-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710056	SCV000965551	pathogenic	Adrenoleukodystrophy	2025-01-21	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 660 of the ABCD1 protein (p.Arg660Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy or adrenomyeloneuropathy (PMID: 7581394, 7825602, 8892025, 10227685, 12175782, 15811009, 20661612, 23835273, 24480483). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585302). 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%. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 9051655). This variant disrupts the p.Arg660 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 11438993, 21889498, 21966424), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000710056	SCV001425349	pathogenic	Adrenoleukodystrophy	2020-03-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268534	SCV001447522	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268534	SCV001768542	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11748843, 10190819, 7581394, 12175782, 31074578, 32091543, 7561948, 29926352, PMC5641780, 7668254, 21476988, 24480483, 23835273, 21068741, 15811009, 8651290, 12624723, 7825602, 31665121, 31101408, 10227685, 20661612, 8892025, 9051655, 30732635, 30902905, 34012265, 32961396, 27535533)
Revvity Omics, Revvity	RCV001268534	SCV002022844	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000710056	SCV002045849	pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000710056	SCV004047497	pathogenic	Adrenoleukodystrophy		criteria provided, single submitter	clinical testing	The ABCD1 c.1978C>T variant has been reported in multiple individuals affected with Adrenoleukodystrophy or adrenomyeloneuropathy (Mallikarjuna et. al., 2019; Matsukawa et. al., 2011) and reported to segregate with disease in a family (Engelen et. al., 2014). Experimental studies have shown that this missense change disrupts ABCD1 enzymatic activity (Yamada et. al., 1997). The p.Arg660Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg660Trp in ABCD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 660 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003392550	SCV004120478	pathogenic	ABCD1-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The ABCD1 c.1978C>T variant is predicted to result in the amino acid substitution p.Arg660Trp. This variant (also known as C2364T) has been documented causative for X-linked adrenoleukodystrophy (ALD) (see, for example, Ligtenberg et al. 1995. PubMed ID: 7825602; Hung et al. 2013. PubMed ID: 23835273; Takano et al. 1999. PubMed ID: 10190819). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.