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

dbSNP: rs193922098

Total submissions: 10

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
Invitae	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 condition	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.