X-153743023-C-T

Position:

• chrX-153743023-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1817C>T​(p.Ser606Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 112,628 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S606P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.91

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

PLXNB3-AS1 (HGNC:40454): (PLXNB3 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-153743023-C-T is Pathogenic according to our data. Variant chrX-153743023-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD1	NM_000033.4	c.1817C>T	p.Ser606Leu	missense_variant	8/10	ENST00000218104.6
ABCD1	XM_047441916.1	c.2117C>T	p.Ser706Leu	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD1	ENST00000218104.6	c.1817C>T	p.Ser606Leu	missense_variant	8/10	1	NM_000033.4	P1
PLXNB3-AS1	ENST00000434284.1	n.72-4445G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112628 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34784

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1087278 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 356298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112628 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34784

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Apr 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 05, 2019	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 03, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2014	- -

Primary adrenocortical insufficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.97		Loss of disorder (P = 0.0205);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs128624225; hg19: chrX-153008477;