Submissions for variant NM_000033.4(ABCD1):c.1876G>A (p.Ala626Thr)

dbSNP: rs1557055316

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699538	SCV000828253	pathogenic	Adrenoleukodystrophy	2024-02-20	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 626 of the ABCD1 protein (p.Ala626Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with the cerebral form of adrenoleukodystrophy (CALD) and/or adrenomyeloneuropathy (AMN) (PMID: 7581394, 7668254, 21700483). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 576910). 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%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001784336	SCV001159930	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	The ABCD1 c.1876G>A; p.Ala626Thr variant is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (Kemp 2001, Park 2018, Watkins 1995). This variant was also found to have occurred de novo in an individual with CALD (Wang 2011). Functional analyses of the variant protein show undetectable protein levels (Kemp 2001). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 626 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.919). Based on available information, the p.Ala626Thr variant is considered to be pathogenic. References: Kemp S et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001 Dec;18(6):499-515. Park JS et al. Spastic paraparesis caused by X-linked adrenoleukodystrophy mimicking vacuolar myelopathy in a human immunodeficiency virus patient: A case report. Medicine (Baltimore). 2018 May;97(20):e10756. Watkins PA et al. Altered expression of ALDP in X-linked adrenoleukodystrophy. Am J Hum Genet. 1995 Aug;57(2):292-301. Wang Y et al. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab. 2011 Sep-Oct;104(1-2):160-6
Institute of Human Genetics, University of Leipzig Medical Center	RCV000699538	SCV001429261	pathogenic	Adrenoleukodystrophy	2023-11-16	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PS2_MOD,PS3_SUP,PM2_SUP,PM5_SUP,PP3,PP4
Revvity Omics, Revvity	RCV001784336	SCV002018684	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000699538	SCV002045847	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000699538	SCV002547807	pathogenic	Adrenoleukodystrophy	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1876G>A (p.Ala626Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 173670 control chromosomes (gnomAD). c.1876G>A has been reported in the literature in multiple hemizygous individuals affected with Adrenoleukodystrophy (e.g. Kok_1995, Wang_2011, Chen_2019, Kaur_2021). These data indicate that the variant is very likely to be associated with disease. Immunohistochemical analysis of fibroblasts from a patient with the variant has shown that there is a reduction in protein expression (Watkins_1995). Five ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001784336	SCV004014189	pathogenic	not provided	2024-11-08	criteria provided, single submitter	clinical testing	Reported previously in an individual with childhood onset cerebral adrenoleukodystrophy (CALD) (PMID: 7668254); Functional studies of fibroblasts derived from individuals who harbor the p.(A626T) variant show that this variant destabilizes expression of the ALDP protein through decreased peroxisomal beta-oxidation and accumulation of very long-chain fatty acids; staining of these fibroblasts showed an abnormal pattern of ALD protein expression (PMID: 11063720, 9425230); 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: 36380532, 31227335, 11748843, 9425230, 29768358, 34302356, 35076462, 35479665, 11063720, 7668254)
Baylor Genetics	RCV000699538	SCV004204434	pathogenic	Adrenoleukodystrophy	2023-09-05	criteria provided, single submitter	clinical testing