Submissions for variant NM_000033.4(ABCD1):c.1520G>T (p.Gly507Val)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050672	SCV003445860	likely pathogenic	Adrenoleukodystrophy	2022-11-29	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant disrupts the p.Gly507 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16996397, 21068741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 10190819). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 507 of the ABCD1 protein (p.Gly507Val).
Revvity Omics, Revvity	RCV003138475	SCV003824444	uncertain significance	not provided	2021-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003050672	SCV005076337	likely pathogenic	Adrenoleukodystrophy	2024-04-12	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1520G>T (p.Gly507Val) 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. Other variants at the same codon, namely, p.Gly507Asp and p.Gly507Ser have been classified in association with X-linked Adrenoleukodystrophy, supporting the critical relevance of this residue to overall ABCD1 protein function. The variant was absent in 182192 control chromosomes. c.1520G>T has been reported in the literature in at-least one Japanese individual affected with clinically and biochemically confirmed X-linked Adrenoleukodystrophy (example Takano_1999 and mentioned in Dong_2022). 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: 35479665, 10190819). ClinVar contains an entry for this variant (Variation ID: 2138771). Based on the evidence outlined above, the variant was classified as likely pathogenic.