NM_000033.4:c.1817C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.91

Publications

20 publications found

Variant links:

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]

ABCD1 links:

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

PLXNB3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 VariationId is 11310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCD1	NM_000033.4 link	c.1817C>T	p.Ser606Leu	missense_variant	Exon 8 of 10	ENST00000218104.6	NP_000024.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6 link	c.1817C>T	p.Ser606Leu	missense_variant	Exon 8 of 10	1	NM_000033.4	ENSP00000218104.3
PLXNB3-AS1	ENST00000434284.1 link	n.72-4445G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112628

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

162474

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1087278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356298

African (AFR)

AF:

0.00

AC:

AN:

26228

American (AMR)

AF:

0.00

AC:

AN:

34067

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19044

East Asian (EAS)

AF:

0.00

AC:

AN:

29968

South Asian (SAS)

AF:

0.00

AC:

AN:

52682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39627

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2885

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837195

Other (OTH)

AF:

0.00

AC:

AN:

45582

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31023

American (AMR)

AF:

0.00

AC:

AN:

10750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.00

AC:

AN:

2739

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53190

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000389

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adrenoleukodystrophy

Pathogenic:4

Jul 05, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Apr 01, 2024

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

not provided

Pathogenic:4

Aug 07, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jul 24, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Jul 24, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary adrenocortical insufficiency

Pathogenic:1

Aug 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.6

PhyloP100

7.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.92

MutPred

0.97

Loss of disorder (P = 0.0205);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over