Submissions for variant NM_000033.4(ABCD1):c.1165C>T (p.Arg389Cys)

gnomAD frequency: 0.00001  dbSNP: rs128624215

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761215	SCV000891169	likely pathogenic	Adrenoleukodystrophy	2018-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000761215	SCV001418216	likely pathogenic	Adrenoleukodystrophy	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 389 of the ABCD1 protein (p.Arg389Cys). This variant is present in population databases (rs128624215, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary spastic paraplegia and/or adrenoleukodystrophy (PMID: 15800013, 22280810, 30564185, 32307584). ClinVar contains an entry for this variant (Variation ID: 623115). 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. 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: 7581394, 7825602, 8566952, 15811009, 22479560, 24719134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000761215	SCV002045764	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000761215	SCV003922520	likely pathogenic	Adrenoleukodystrophy	2023-03-31	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1165C>T (p.Arg389Cys) 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 allele was found at a frequency of 9e-06 in 111465 control chromosomes (gnomAD v3.1.2). c.1165C>T has been reported in the literature in several hemizygous individuals affected with Adrenoleukodystrophy and Adrenomyeloneuropathy (e.g. Asheuer_2005, Salsano_2012, D'Amore_2018, Benzoni_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and four as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004588164	SCV005079945	likely pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	Reported previously in five asymptomatic females carriers from one family who had three affected relatives with adrenoleukodystrophy who did not pursue genetic testing (PMID: 22280810); Reported as a hemizygous variant in a 70 year old male with mildly elevated VLCFA, subclinical findings of diffuse deep tendon hyperreflexia, but without adrenal insufficiency or other features of X-ALD (PMID: 32307584); Reported previously in two brothers with adrenoleukodystrophy and a positive family history; however, no further clinical or segregation information was provided (PMID: 36991579); Not observed at a 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: 15800013, 30564185, 35013584, 34754073, 32632637, 22280810, 32307584, 24719134, 24480483, 15811009, 36991579)
Natera, Inc.	RCV000761215	SCV002084628	uncertain significance	Adrenoleukodystrophy	2021-06-02	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000761215	SCV002583446	likely pathogenic	Adrenoleukodystrophy	2022-05-02	no assertion criteria provided	clinical testing