Submissions for variant NM_000033.4(ABCD1):c.2065C>T (p.Arg689Cys)

gnomAD frequency: 0.00005  dbSNP: rs782376163

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435174	SCV000528868	uncertain significance	not provided	2018-02-02	criteria provided, single submitter	clinical testing	The R689C variant in the ABCD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, it is listed in the X-linked ALD database as a variant of uncertain significance (ALD database, 2016). The R689C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R689C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L684P, T693M) have been reported in the Human Gene Mutation Database in association with ABCD1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R689C as a variant of uncertain significance.
Invitae	RCV001247652	SCV001421088	uncertain significance	Adrenoleukodystrophy	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 689 of the ABCD1 protein (p.Arg689Cys). 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 variant has not been reported in the literature in individuals affected with ABCD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 387013). 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 not expected to disrupt ABCD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001247652	SCV002045798	uncertain significance	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155179	SCV003844770	uncertain significance	not specified	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.2065C>T (p.Arg689Cys) 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 allele was found at a frequency of 6.9e-05 in 158308 control chromosomes, including 2 hemizygotes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ABCD1 causing Adrenoleukodystrophy (6.9e-05 vs 0.004), allowing no conclusion about variant significance. To our knowledge, c.2065C>T has not been reported in the literature in individuals affected with Adrenoleukodystrophy and no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001247652	SCV002084661	uncertain significance	Adrenoleukodystrophy	2019-10-28	no assertion criteria provided	clinical testing