ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1849C>T (p.Arg617Cys) (rs4010613)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012065 SCV000963499 pathogenic Adrenoleukodystrophy 2020-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 617 of the ABCD1 protein (p.Arg617Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg617 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 7581394, 8040304, 9425230, 17542813, 21068741, 21700483), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 Praxis fuer Humangenetik 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 RCV001284826 SCV001470865 pathogenic none 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
OMIM RCV000012065 SCV000032299 pathogenic Adrenoleukodystrophy 1994-08-01 no assertion criteria provided literature only

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