Submissions for variant NM_000033.4(ABCD1):c.1628C>T (p.Pro543Leu)

dbSNP: rs1557054776

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633485	SCV000754718	pathogenic	Adrenoleukodystrophy	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 543 of the ABCD1 protein (p.Pro543Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenoleukodystrophy (ALD) and late-onset neurological symptoms (PMID: 9242200, 10737980, 10980539, 11748843, 15811009, 24480483, 24788897). ClinVar contains an entry for this variant (Variation ID: 528341). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. Experimental studies have shown that this missense change affects ABCD1 function (PMID: 11748843, 27067449). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000727694	SCV000855037	pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727694	SCV000883320	pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing	The ABCD1 c.1628C>T; p.Pro543Leu variant has been described in several individuals affected with adrenoleukodystrophy (ALD) with no detectable level of peroxisomal ABC half-transporter (ALDP) in their cells (see link to ALD ABCD1 database and references therein). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 543 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Another variant at this codon (c.1627C>T; p.Pro543Ser) has been identified in patients with ALD and is considered pathogenic (see link to ALD ABCD1 database and references therein). Based on available information, the p.Pro543Leu variant is considered pathogenic. References: ALD ABCD1 Database: http://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1
Athena Diagnostics	RCV000727694	SCV001475502	likely pathogenic	not provided	2020-03-31	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Found in multiple individuals with expected phenotype for this gene.
Revvity Omics, Revvity	RCV000727694	SCV002022866	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000633485	SCV002045835	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000727694	SCV004036881	pathogenic	not provided	2023-09-21	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: 34826210, 10980539, 10737980, 31418856, 32938577, 25488625, 9242200, 23768953, 11748843, 15811009, 16672758, 24788897, 24480483, 27067449, 30697666, 12402273, 9553942, 34997422)