ClinVar Genomic variation as it relates to human health

Variant summary: ABCD1 c.1552C>T (p.Arg518Trp) results in a non-conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 177823 control chromosomes (gnomAD and publication). c.1552C>T has been reported in the literature in multiple individuals affected with Adrenoleukodystrophy including symptomatic female carriers (Chu_2015, Fanen_1994, Feigenbaum_1996, Guettsches_2010, Guimaraes_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

ABCD1 NM_000033.3 exon 6 p.Arg518Trp (c.1552C>T): This variant has been reported in the literature in at least 3 individuals with a clinical diagnosis or features of adrenoleukodystrophy (ALD), segregating with disease in at least 1 affected family member (Fanen 1994 PMID:8040304, Guettsches 2010 PMID:20195870, Shimozawa 2011 PMID:21068741). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:11307). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this same codon (p.Arg518Pro, p.Arg518Gly, p.Arg518Gln) have been reported in the literature, suggesting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg518 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10190819, 12175782, 15811009, 16087056, 21068741, 23419472, 23566833, 26260157). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function. ClinVar contains an entry for this variant (Variation ID: 11307). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 8651290, 12175782, 20661612, 26454440). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 518 of the ABCD1 protein (p.Arg518Trp).

PM2_Supporting+PS4_Moderate+PM5+PP3_Moderate+PP4

The ABCD1 p.Arg518Trp variant was identified in 5 of 318 proband chromosomes (frequency: 0.02) from individuals or families with X-linked adrenoleukodystrophy, and was not identified in 200 control chromosomes from healthy individuals (Chu 2015, Fanen 1994, Matsukawa 2010, Feigenbaum 1996). The variant was also found in case study by Guettsches (2010) in two symptomatic adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) female carriers. The son of one of the carriers died of ALD at age of 9. The variant was identified in dSNP (rs128624224) as "With Pathogenic allele", ClinVar (classified as pathogenic by OMIM and EGL genetic Diagnistics), the ALD Mutation Database (as pathogenic, identified in 19 ALD patients; no detectable ALDP in patient cells) and LOVD (as likely pathogenic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The protein analysis study by Feigenbaum (1996) identifies the variant resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. The p.Arg518 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.