Submissions for variant NM_000033.4(ABCD1):c.839G>A (p.Arg280His)

dbSNP: rs781904944

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226321	SCV001398632	pathogenic	Adrenoleukodystrophy	2023-12-30	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 280 of the ABCD1 protein (p.Arg280His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biochemical features of X-linked adrenoleukodystrophy (PMID: 35076462; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 953948). 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%. This variant disrupts the p.Arg280 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748843, 15811009, 29443243; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001587256	SCV001824251	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported in individuals with a positive newborn screening result for X-ALD; however follow up clinical and biochemical information was not provided (Matteson et al., 2021; Burton et al., 2022); This variant is associated with the following publications: (PMID: 29443243, 15811009, 11748843, 35076462, 33920672)
3billion	RCV001226321	SCV002012135	likely pathogenic	Adrenoleukodystrophy	2021-10-02	criteria provided, single submitter	clinical testing	The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg280Cys) has been reported as pathogenic (PMID:15811009 PM5). Missense changes are a common disease-causing mechanism (PP2).. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001226321	SCV002041842	likely pathogenic	Adrenoleukodystrophy	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.839G>A (p.Arg280His) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants affecting the same amino acid residue (R280C/R280H/R280L/R280P) are associated with Adenoleukodystrophy in the HGMD database supporting the possible functional relevance of this conserved residue to overall function. The variant was absent in 128937 control chromosomes (gnomAD). c.839G>A has been reported in the literature in at-least 5 male individuals as part of the California (example, Matteson_2021) and Illinois (Burton_2022) states Adrenoleukodystrophy newborn screening programs. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001226321	SCV002045759	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001587256	SCV003823070	likely pathogenic	not provided	2023-11-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398972	SCV004120592	likely pathogenic	ABCD1-related disorder	2022-11-08	criteria provided, single submitter	clinical testing	The ABCD1 c.839G>A variant is predicted to result in the amino acid substitution p.Arg280His. This variant has been reported in multiple individuals with X-linked adrenoleukodystrophy, and biochemical studies support its pathogenicity (Burton et al. 2022. PubMed ID: 35076462; Matteson et al. 2021. PubMed ID: 33920672). Further, three alternate missense substitutions at the same amino acid position have been reported as causative for X-linked adrenoleukodystrophy (p.Arg280Cys, Coll et al. 2005. PubMed ID: 15811009; p.Arg280Leu, Lan. 2001. PubMed ID: 11798073; p.Arg280Pro, Mahdieh et al. 2021. PubMed ID: 33547378). This variant has also been reported in other affected individuals tested at PreventionGenetics. 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 likely pathogenic.
Baylor Genetics	RCV001226321	SCV004207683	likely pathogenic	Adrenoleukodystrophy	2023-12-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001226321	SCV002084615	uncertain significance	Adrenoleukodystrophy	2020-02-10	no assertion criteria provided	clinical testing