Submissions for variant NM_000033.4(ABCD1):c.488G>A (p.Arg163His)

dbSNP: rs1057517954

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414525	SCV000491176	likely pathogenic	not provided	2016-06-03	criteria provided, single submitter	clinical testing	The R163H variant in the ABCD1 gene has been reported previously in association with X-linked adrenoleukodystrophy in a symptomatic female carrier (Ligtenberg et al., 1995). The R163H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R163H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (L158P, L160P, S161P, R163P, R163L, R163G) have been reported in the Human Gene Mutation Database in association with adrenoleukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R163H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699535	SCV000828250	pathogenic	Adrenoleukodystrophy	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 163 of the ABCD1 protein (p.Arg163His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 7825602; internal data). ClinVar contains an entry for this variant (Variation ID: 372736). 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%. This variant disrupts the p.Arg163 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 10980309, 25324868, 26227820), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000414525	SCV002023961	likely pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338970	SCV002635746	likely pathogenic	Inborn genetic diseases	2017-10-09	criteria provided, single submitter	clinical testing	The p.R163H variant (also known as c.488G>A), located in coding exon 1 of the ABCD1 gene, results from a G to A substitution at nucleotide position 488. The arginine at codon 163 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in a symptomatic female with elevated very long chain fatty acids (Ligtenberg MJ et al. Am. J. Hum. Genet., 1995 Jan;56:44-50). Based on structural analysis, this variant disrupts transmembrane domain structure and changes the binding affinity with PEX19 (Aller SG et al. Science, 2009 Mar;323:1718-22; Perez C et al. Nature, 2015 Aug;524:433-8; Li N et al. Cell, 2017 Jan;168:101-110.e10; Morgan JL et al. Structure, 2017 Mar;25:522-529). 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.
Natera, Inc.	RCV000699535	SCV002084603	likely pathogenic	Adrenoleukodystrophy	2020-08-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004730940	SCV005339876	likely pathogenic	ABCD1-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The ABCD1 c.488G>A variant is predicted to result in the amino acid substitution p.Arg163His. This variant was reported in an individual with adrenoleukodystrophy (ALD) (Ligtenberg et al. 1995. PubMed ID: 7825602). Alternate nucleotide changes affecting the same amino acid (p.Arg163Pro, p.Arg163Leu, p.Arg163Gly, p.Arg163Cys) have been reported in individuals affected with ALD (Ohi et al. 2000. PubMed ID: 10980309; Jwa et al. 2014. PubMed ID: 25324868; Ogaki et al. 2015. PubMed ID: 26227820; Wiens et al. 2019. PubMed ID: 31074578). This variant occurs within the trans-membrane domain (TMD) in exon 1 where pathogenic variants are known to cluster (Chu et al. 2015. PubMed ID: 26454440; Kemp et al. 2001. PubMed ID: 11748843). This variant has not been reported in a large population database, indicating this variant is rare. The c.488G>A variant is interpreted as likely pathogenic.