Submissions for variant NM_000033.4(ABCD1):c.1817C>T (p.Ser606Leu)

gnomAD frequency: 0.00001  dbSNP: rs128624225

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000517966	SCV000232463	pathogenic	not provided	2014-08-07	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000517966	SCV000612232	pathogenic	not provided	2017-07-24	criteria provided, single submitter	clinical testing
Invitae	RCV000180094	SCV000629995	pathogenic	Adrenoleukodystrophy	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 606 of the ABCD1 protein (p.Ser606Leu). 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 individuals with various forms of X-linked adrenoleukodystrophy including Addison's disease and adrenomyeloneuropathy (PMID: 7581394, 8040304, 10190819, 12624723, 14767898, 15811009, 22479560). ClinVar contains an entry for this variant (Variation ID: 11310). 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 have shown that this missense change affects ABCD1 function (PMID: 11248239, 12530690, 17542813). This variant disrupts the p.Ser606 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8651290, 21700483, 21966424, 22479560). 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	RCV000180094	SCV000998462	pathogenic	Adrenoleukodystrophy	2019-07-05	criteria provided, single submitter	clinical testing	This previously reported variant (rs128624225) has been identified in multiple patients with clinical and biochemical findings consistent with ABCD1 related disease. Four submitters in ClinVar classify this variant as pathogenic. Additionally, functional analysis supports the deleterious effect of this this variant on protein function. This variant is considered pathogenic.
GeneDx	RCV000517966	SCV001796975	pathogenic	not provided	2020-07-24	criteria provided, single submitter	clinical testing	Functional analysis has shown that S606L decreases ATP-binding affinity of the protein; and expression studies of the mutant S606L protein in ALDP negative fibroblasts show very low expression of S606L compared with wild type expression controls (Roerig et al., 2001; Takahashi et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11248239, 16087056, 7581394, 12530690, 12624723, 30343438, 8040304, 15811009, 17973979, 17092750, 22479560, 10190819, 11748843, 17542813, 21476988, 31526374)
Genome-Nilou Lab	RCV000180094	SCV002045840	pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000517966	SCV002049786	pathogenic	not provided	2020-12-03	criteria provided, single submitter	clinical testing	The ABCD1 c.1817C>T; p.Ser606Leu variant is reported in the literature in at least 30 individuals affected with various forms of adrenoleukodystrophy including adrenomyeloneuropathy (see ALD database link, Pan 2004, Li 2019). In vitro functional analyses demonstrate that this variant reduces the ATP-binding capacity of the ALDP protein (Gartner 2002, Roerig 2001), and results in the degradation of the protein post translation (Takahashi 2007). This variant is found on a single chromosome in the non-Finnish European population (1/184572 alleles) in the Genome Aggregation Database. The serine at codon 606 is located in the ATP-binding domain and is highly conserved among ABC transporter superfamily genes (Fanen 1994), and computational analyses predict that this variant is deleterious (REVEL: 0.935). Based on available information, this variant is considered to be pathogenic. References: ALD ABCD1 Mutation Database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 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. Gartner J et al. Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis. Endocr Res. 2002 Nov;28(4):741-8. Pan H et al. ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy. Pediatr Neurol. 2005 Aug;33(2):114-20. doi: 10.1016/j.pediatrneurol.2005.03.006. PMID: 16087056. Li J et al. Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy. BMC Neurol. 2019 Sep 16;19(1):227. Roerig P et al. Characterization and functional analysis of the nucleotide binding fold in human peroxisomal ATP binding cassette transporters. FEBS Lett. 2001 Mar 9;492(1-2):66-72. Takahashi N et al. Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations. J Neurochem. 2007 Jun;101(6):1632-43.
OMIM	RCV000012062	SCV000032296	pathogenic	Primary adrenocortical insufficiency	1994-08-01	no assertion criteria provided	literature only