ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.346G>A (p.Gly116Arg)

dbSNP: rs398123110
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000077963 SCV000109792 pathogenic not provided 2013-04-12 criteria provided, single submitter clinical testing
GeneDx RCV000077963 SCV002549265 pathogenic not provided 2022-04-08 criteria provided, single submitter clinical testing Functional analysis found this variant was associated with significantly reduced ABCD1 enzyme activity compared to wild-type (Takahashi N et al., 2007); Not observed 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: 22045812, 10737980, 8651290, 32101828, 17542813, 31526374)
Ambry Genetics RCV002460043 SCV002618443 likely pathogenic Inborn genetic diseases 2018-12-12 criteria provided, single submitter clinical testing The p.G116R variant (also known as c.346G>A), located in coding exon 1 of the ABCD1 gene, results from a G to A substitution at nucleotide position 346. The glycine at codon 116 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected twice in individuals with x-linked adrenoleukodystrophy and/or adrenomyeloneuropathy (Feigenbaum V et al. Am. J. Hum. Genet., 1996 Jun;58:1135-44; Lachtermacher MB et al. Hum. Mutat., 2000;15:348-53). In one functional study this alteration was shown to severely impair very long chain fatty acid (VLFFA) beta-oxidation (Takahashi N et al. J. Neurochem., 2007 Jun;101:1632-43). In addition, a different alteration located at the same position, p.G116E, has been detected in Japanese individuals with x-linked adrenoleukodystrophy (Matsumoto T et al. J. Hum. Genet., 2003;48:125-9; Miyoshi Y et al. Endocr. J., 2010 Sep;57:965-72).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.
Invitae RCV002513815 SCV003443989 pathogenic Adrenoleukodystrophy 2023-12-04 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the ABCD1 protein (p.Gly116Arg). 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: 8651290, 10737980, 31526374, 32101828). ClinVar contains an entry for this variant (Variation ID: 92325). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 17542813). For these reasons, this variant has been classified as Pathogenic.

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