Submissions for variant NM_000033.4(ABCD1):c.1849C>T (p.Arg617Cys)

dbSNP: rs4010613

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012065	SCV000963499	pathogenic	Adrenoleukodystrophy	2024-01-16	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 617 of the ABCD1 protein (p.Arg617Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked adrenoleukodystrophy and Addison's disease (PMID: 7825602, 8040304, 8566952, 15811009, 16087056, 17029209). ClinVar contains an entry for this variant (Variation ID: 11313). 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.Arg617 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581394, 8040304, 9425230, 17542813, 21068741, 21700483). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000012065	SCV001167298	pathogenic	Adrenoleukodystrophy	2019-11-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093003	SCV001249772	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012065	SCV001429430	likely pathogenic	Adrenoleukodystrophy	2018-10-22	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001093003	SCV001470865	pathogenic	not provided	2019-09-27	criteria provided, single submitter	clinical testing	The ABCD1 c.1849C>T; p.Arg617Cys variant (rs4010613) is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (X-ALD) (Coll 2005, Fanen 1994, Kemp 2001, Krasemann 1996, Lan 2011, Ligtenberg 1995, Pan 2005). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 617 is highly conserved, it occurs in the ABCD1 nucleotide binding fold (Fanen 1994), and functional studies of patient fibroblasts with this variant suggest loss of protein expression (Kemp 2001). Additionally, other amino acid substitutions at this codon (Gly, His, Leu) have been reported in individuals with X-ALD and are considered disease-causing (Coll 2005, Fanen 1994, Kemp 2001, Krasemann 1996, Lan 2011, Pan 2005). Based on available information, the p.Arg617Cys variant is considered to be pathogenic. References: 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. Fanen P et al. Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene. J Clin Invest. 1994 Aug;94(2):516-20. Kemp S et al. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001 Dec;18(6):499-515. Krasemann EW et al. Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet. 1996 Feb;97(2):194-7. Lan F et al. Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations. Clin Chim Acta. 2011 May 12;412(11-12):970-4. Ligtenberg MJ et al. Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am J Hum Genet. 1995 Jan;56(1):44-50. Pan H et al. ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy. Pediatr Neurol. 2005 Aug;33(2):114-20.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000012065	SCV001482532	pathogenic	Adrenoleukodystrophy	2021-01-22	criteria provided, single submitter	research	ACMG codes:PS4, PM1, PM2, PP2, PP3, PP5
Genome-Nilou Lab	RCV000012065	SCV002045843	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001093003	SCV003813028	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000012065	SCV004814244	pathogenic	Adrenoleukodystrophy	2021-01-08	criteria provided, single submitter	clinical testing	Criteria Codes: PS3 PS4_Mod PM2 PM5 PP3 PP4
OMIM	RCV000012065	SCV000032299	pathogenic	Adrenoleukodystrophy	1994-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000012065	SCV002084654	pathogenic	Adrenoleukodystrophy	2017-11-28	no assertion criteria provided	clinical testing