Submissions for variant NM_000033.4(ABCD1):c.1166G>A (p.Arg389His)

dbSNP: rs886044777

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000268436	SCV000612225	likely pathogenic	not provided	2019-06-05	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/205134 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Statistically enriched in patients compared to ethnically matched controls. Results on protein functions were inconclusive.
Eurofins Ntd Llc (ga)	RCV000268436	SCV000700868	pathogenic	not provided	2017-06-13	criteria provided, single submitter	clinical testing
Invitae	RCV000984141	SCV001198016	pathogenic	Adrenoleukodystrophy	2023-09-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 8566952, 15811009, 22479560). 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: 281336). This missense change has been observed in individuals with ABCD1-related disease (PMID: 7581394, 7825602, 15811009, 24719134). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCD1 protein (p.Arg389His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984141	SCV001361104	pathogenic	Adrenoleukodystrophy	2021-08-24	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1166G>A (p.Arg389His) results in a non-conservative amino acid change in 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 183351 control chromosomes. c.1166G>A has been reported in the literature in multiple individuals affected with ABCD1-related diseases (Coll_2005, Kemp_1995, Kok_1995, Hodapp_2006, Engelen_2014, Matteson_2021). These data indicate that the variant is very likely to be associated with disease. In functional studies compared to controls, the variant showed less than 50% of peroxisomal beta-oxidation activity and approximately 40% of ALDP protein levels (Schackmann_2016, Zhang_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000984141	SCV002045819	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000268436	SCV004031738	pathogenic	not provided	2023-08-30	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: 8892025, 34649108, 16401743, 7668254, 21476988, 9242200, 7581394, 15811009, 7825602, 30732635, 27067449, 31526374, 24480483, 24719134, 34946879, 10551832, 27535533)
PreventionGenetics, part of Exact Sciences	RCV003391027	SCV004120525	pathogenic	ABCD1-related condition	2023-02-06	criteria provided, single submitter	clinical testing	The ABCD1 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple patients with X-linked adrenoleukodystrophy (Kok et al. 1995. PubMed ID: 7581394; Ligtenberg et al. 1995. PubMed ID: 7825602; Schackmann et al. 2016. PubMed ID: 27067449). 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.
Counsyl	RCV000984141	SCV001132113	likely pathogenic	Adrenoleukodystrophy	2017-05-09	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000268436	SCV001743456	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000268436	SCV001958731	likely pathogenic	not provided		no assertion criteria provided	clinical testing