ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.838C>T (p.Arg280Cys)

dbSNP: rs193922098
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029290 SCV000051936 likely pathogenic Adrenoleukodystrophy 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Ambry Genetics RCV000721083 SCV000851969 pathogenic History of neurodevelopmental disorder 2013-06-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000029290 SCV000948152 pathogenic Adrenoleukodystrophy 2023-12-01 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 280 of the ABCD1 protein (p.Arg280Cys). 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: 11748843, 15811009; Invitae; https//adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). ClinVar contains an entry for this variant (Variation ID: 35643). 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%. This variant disrupts the p.Arg280 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 11798073), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000029290 SCV000996044 pathogenic Adrenoleukodystrophy 2019-05-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001781320 SCV001474333 likely pathogenic not provided 2020-06-18 criteria provided, single submitter clinical testing The ABCD1 c.838C>T; p.Arg280Cys variant (rs193922098) is reported in several individuals with X-linked adrenoleukodystrophy and increased very-long-chain fatty acids (see link to ABCD1 variant database, Coll 2005, Isaacs 2014). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 35643) and is reported in the general population in 2 out of 128,935 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 280 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Link to ABCD1 database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Coll MJ et al. X-linked Adrenoleukodystrophy in Spain. Identification of 26 Novel Mutations in the ABCD1 Gene in 80 Patients. Improvement of Genetic Counseling in 162 Relative Females. Clin Genet. 2005 May;67(5):418-24. Isaacs D et al. Adult-onset Adrenoleukodystrophy Presenting After Chemotherapy: No Black and White Matter. Neurol Clin Pract. 2014 Apr;4(2):168-170.
Revvity Omics, Revvity RCV001781320 SCV002023955 likely pathogenic not provided 2022-04-25 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000029290 SCV002045815 pathogenic Adrenoleukodystrophy 2021-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000029290 SCV002811710 pathogenic Adrenoleukodystrophy 2022-03-17 criteria provided, single submitter clinical testing
GeneDx RCV001781320 SCV004028109 likely pathogenic not provided 2023-08-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29443243, 11748843, 33920672, 35466195, 35076462, 36076658, 15811009)
PreventionGenetics, part of Exact Sciences RCV003407363 SCV004113275 pathogenic ABCD1-related disorder 2023-06-06 criteria provided, single submitter clinical testing The ABCD1 c.838C>T variant is predicted to result in the amino acid substitution p.Arg280Cys. This variant has been reported in multiple unrelated individuals with adrenoleukodystrophy (Kemp et al. 2001. PubMed ID: 11748843; Coll et al. 2005. PubMed ID: 15811009; Isaacs et al. 2014. PubMed ID: 29443243). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-152991559-C-T). This variant is interpreted as pathogenic.
Baylor Genetics RCV000029290 SCV005049415 pathogenic Adrenoleukodystrophy 2024-03-27 criteria provided, single submitter clinical testing

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