Submissions for variant NM_000033.4(ABCD1):c.1597A>C (p.Lys533Gln)

gnomAD frequency: 0.00001  dbSNP: rs781862879

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761217	SCV000891171	likely pathogenic	Adrenoleukodystrophy	2017-08-16	criteria provided, single submitter	clinical testing
Invitae	RCV000761217	SCV001588544	pathogenic	Adrenoleukodystrophy	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 533 of the ABCD1 protein (p.Lys533Gln). This variant is present in population databases (rs781862879, gnomAD 0.01%). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 11748843, 31074578; TheALDMutationDatabase). ClinVar contains an entry for this variant (Variation ID: 623117). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. This variant disrupts the p.Lys533 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been observed in individuals with ABCD1-related conditions (PMID: 15811009, 28991658; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000761217	SCV002045833	likely pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000761217	SCV002103356	pathogenic	Adrenoleukodystrophy	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1597A>C (p.Lys533Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182895 control chromosomes. c.1597A>C has been reported in the literature as a likely pathogenic variant detected in settings of newborn screening (NBS) programs in infants with screen positive findings of elevated very long chain fatty acid levels (C26:0) (example, Wiens_2019, va de Stadt_2021, Matteson_2021). Some of these cases were reported as having no ALD symptoms (example, van de Stadt_2021), while others were reported as tentatively resolved cases of ALD (example, Matteson_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although one study demonstrated an absence of ALD protein product by immunoblotting (example, van de Stadt_2021). Additionally, another variant (p.Lys533Glu) is internally classified as likely pathogenic, suggesting functional importance of this resdue. The following publications have been ascertained in the context of this evaluation (PMID: 31074578, 33920672, 34946879). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002397532	SCV002709030	likely pathogenic	Inborn genetic diseases	2020-08-03	criteria provided, single submitter	clinical testing	The p.K533Q variant (also known as c.1597A>C), located in coding exon 6 of the ABCD1 gene, results from an A to C substitution at nucleotide position 1597. The lysine at codon 533 is replaced by glutamine, an amino acid with similar properties. This variant was detected in multiple individuals with a clinical diagnosis of X-linked adrenoleukodystrophy (X-ALD) (Wiens K et al. Am. J. Med. Genet. A, 2019 07;179:1205-1213; Ambry internal data). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, three other alterations at the same codon, p.K533E (c.1597A>G), p.K533N (c.1599G>T), and p.K533R (c.1598A>G) have been described in patients with X-ALD (Coll MJ et al. Clin. Genet., 2005 May;67:418-24; Tsuboi T et al. J. Neurol. Sci., 2017 10;381:107-109; Richter JE et al. Case Rep Genet, 2020 Jan;2020:3256539). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000761217	SCV002787269	pathogenic	Adrenoleukodystrophy	2021-09-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003141741	SCV003821538	likely pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV003141741	SCV004030659	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31074578, 33920672, 32047678, 15811009, 34946879)
Baylor Genetics	RCV000761217	SCV004203760	likely pathogenic	Adrenoleukodystrophy	2023-10-26	criteria provided, single submitter	clinical testing