Submissions for variant NM_000033.4(ABCD1):c.823C>T (p.Arg275Trp)

gnomAD frequency: 0.00001  dbSNP: rs782083931

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000434855	SCV000525476	likely pathogenic	not provided	2024-01-31	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: 37977233, 31074578, 33920672)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507685	SCV000602346	uncertain significance	not specified	2017-03-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695726	SCV000824241	likely pathogenic	Adrenoleukodystrophy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the ABCD1 protein (p.Arg275Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 31074578; Invitae). It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 384589). 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) has been performed at Invitae 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. 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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000695726	SCV000891168	likely pathogenic	Adrenoleukodystrophy	2017-09-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000434855	SCV002023962	likely pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000695726	SCV002045758	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411343	SCV002676091	uncertain significance	Inborn genetic diseases	2017-07-17	criteria provided, single submitter	clinical testing	The p.R275W variant (also known as c.823C>T), located in coding exon 1 of the ABCD1 gene, results from a C to T substitution at nucleotide position 823. The arginine at codon 275 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000695726	SCV005395661	likely pathogenic	Adrenoleukodystrophy	2024-09-05	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.823C>T (p.Arg275Trp) 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. The variant allele was found at a frequency of 7.4e-06 in 135103 control chromosomes. c.823C>T has been reported in the literature in at least 2 individuals affected with clinical features of ABCD1-related conditions and multiple individuals testing positive for X-ALD on newborn screening (example, Beil_2023, Weins_2019, Tang_2024, Matteson_2021). Further, multiple variants have been reportedly associated with disease in this region of the protein, suggesting a possible hotspot. 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. The following publications have been ascertained in the context of this evaluation (PMID: 33920672, 31074578, 37977233). ClinVar contains an entry for this variant (Variation ID: 384589). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003902547	SCV004721300	uncertain significance	ABCD1-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The ABCD1 c.823C>T variant is predicted to result in the amino acid substitution p.Arg275Trp. This variant has been reported in the hemizygous state in multiple individuals with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Wiens et al 2019. PubMed ID: 31074578; Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). However, this variant has also been reported in the hemizygous state in unaffected individuals (Beil et al. 2023. DOI:https://doi.org/10.1016/j.gimo.2023.100012). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent, including one hemizygote, in gnomAD. An alternate nucleotide affecting the same amino acid (p.Arg275Pro), has been reported in the hemizygous state in an individual with a positive newborn screen for X-linked adrenoleukodystrophy (Table 1, Priestley et al. 2022. PubMed ID: 35466195). Although we suspect that the c.823C>T (p.Arg275Trp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.