Submissions for variant NM_000033.4(ABCD1):c.1900G>A (p.Ala634Thr)

dbSNP: rs782041940

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000488080	SCV000333612	uncertain significance	not provided	2015-08-18	criteria provided, single submitter	clinical testing
Invitae	RCV000633484	SCV000754717	likely pathogenic	Adrenoleukodystrophy	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 634 of the ABCD1 protein (p.Ala634Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy (PMID: 35076462; external communication). ClinVar contains an entry for this variant (Variation ID: 282253). 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%. 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000633484	SCV000992324	uncertain significance	Adrenoleukodystrophy	2019-03-28	criteria provided, single submitter	clinical testing	This ABCD1 variant is absent from large population datasets and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classifies it as likely pathogenic and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this variant may create a potential cryptic splice site, however, its effect on splicing has not been studied experimentally to our knowledge. The clinical significance of c.1900G>A is uncertain at this time.
Genome-Nilou Lab	RCV000633484	SCV002045774	uncertain significance	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000488080	SCV002513080	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Reported in a male with a borderline newborn screen for X-ALD in the published literature; Classified as a variant of uncertain significance in two individuals with a positive newborn screen for X-ALD (Matteson et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34946879, 35076462, 33920672, 34506099)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000633484	SCV002549829	uncertain significance	Adrenoleukodystrophy	2022-06-20	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous._x000D_ Criteria applied: PS4_MOD, PM2_SUP, PP3
Revvity Omics, Revvity	RCV000488080	SCV003824432	uncertain significance	not provided	2023-11-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401238	SCV004102981	uncertain significance	ABCD1-related condition	2023-11-18	criteria provided, single submitter	clinical testing	The ABCD1 c.1900G>A variant is predicted to result in the amino acid substitution p.Ala634Thr. This variant was reported in individuals with borderline adrenoleukodystrophy, but was classified as a variant of uncertain significance (Burton et al. 2022. PubMed ID: 35076462; Supplemental table, Matteson et al. 2021. PubMed ID: 33920672; https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). Functional studies in fibroblasts suggest this variant impacts ABCD1 activity (van de Stadt et al. 2021. PubMed ID: 34946879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While we suspect that this variant could be pathogenic, at this time we interpret its clinical significance as uncertain due to insufficient functional and genetic evidence.
Natera, Inc.	RCV000633484	SCV002084658	uncertain significance	Adrenoleukodystrophy	2020-10-12	no assertion criteria provided	clinical testing