Submissions for variant NM_000033.4(ABCD1):c.1979G>A (p.Arg660Gln)

dbSNP: rs1557055340

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778893	SCV000915296	likely pathogenic	Adrenoleukodystrophy	2017-10-20	criteria provided, single submitter	clinical testing	The ABCD1 c.1979G>A (p.Arg660Gln) missense variant has been reported in at least two studies and is found in a hemizygous state in a total of three individuals with adrenoleukodystrophy (Kumar et al. 2011; Shukla et al. 2011). All three individuals had high plasma very-long-chain fatty acids and onset of symptoms before age five. The p.Arg660Gln variant was absent from 120 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Arg660Gln variant is classified as a likely pathogenic for X-linked adrenoleukodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000778893	SCV001583671	uncertain significance	Adrenoleukodystrophy	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 660 of the ABCD1 protein (p.Arg660Gln). 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: 21966424). In some individuals this variant is observed in cis (on the same chromosome) with the silent variant p.Ala650Ala (PMID: 21889498). 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: 632051). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCD1 function (PMID: 21966424, 34946879). This variant disrupts the p.Arg660 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7825602, 9051655, 24480483). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000778893	SCV001934339	likely pathogenic	Adrenoleukodystrophy	2020-11-27	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous.
Genome-Nilou Lab	RCV000778893	SCV002045850	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778893	SCV002768864	pathogenic	Adrenoleukodystrophy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with adrenoleukodystrophy (MIM#300100) (PMIDs: 11063720, 17542813). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Variants p.(Arg660Trp) and p.(Arg660Pro) have been reported >30 times and 1 time respectively in patients with adrenoleukodystrophy (ClinVar, The ALD Mutation Database, PMID: 11438993) (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least 3 patients with adrenoleukodystrophy (ClinVar, The ALD Mutation Database, PMIDs:21889498, 21966424). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The adrenoleukodystrophy protein level was not detected via western blot (PMID: 21966424). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000778893	SCV004100201	likely pathogenic	Adrenoleukodystrophy	2023-09-27	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1979G>A (p.Arg660Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense variant is classified as pathogenic (p.Arg660Trp). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 138140 control chromosomes (gnomAD). c.1979G>A has been reported in the literature in individuals affected with Adrenoleukodystrophy (Kumar_2011, Shukla_2011). 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: 21966424, 21889498, 34946879). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003457795	SCV004184954	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ABCD1: PM1, PM2, PM5, PS4:Moderate, PP3