rs387906494

Positions:

• chrX-153737177-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000033.4(ABCD1):​c.1415_1416del​(p.Gln472ArgfsTer83) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000456 in 1,097,595 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: ABCD1 NM_000033.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 6.81

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]

LOC124905226 (HGNC:):

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

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153737177-CAG-C is Pathogenic according to our data. Variant chrX-153737177-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 11303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153737177-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCD1	NM_000033.4	c.1415_1416del	p.Gln472ArgfsTer83	frameshift_variant	5/10	ENST00000218104.6	NP_000024.2
LOC124905226	XR_007068350.1	n.3172_3173del		non_coding_transcript_exon_variant	2/2
ABCD1	XM_047441916.1	c.1715_1716del	p.Gln572ArgfsTer83	frameshift_variant	6/11		XP_047297872.1
ABCD1	XM_047441917.1	c.1471_1472del	p.Arg491GlyfsTer?	frameshift_variant	6/8		XP_047297873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCD1	ENST00000218104.6	c.1415_1416del	p.Gln472ArgfsTer83	frameshift_variant	5/10	1	NM_000033.4	ENSP00000218104	P1
PLXNB3-AS1	ENST00000434284.1	n.580+891_580+892del		intron_variant, non_coding_transcript_variant		3
ABCD1	ENST00000443684.2	n.418_419del		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097595 Hom.: 0 AF XY: 0.00000275 AC XY: 1 AN XY: 363143

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adrenoleukodystrophy Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change creates a premature translational stop signal (p.Gln472Argfs*83) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with childhood or adult-onset adrenoleukodystrophy or adrenomyeloneuropathy (PMID: 7849723, 8048932, 22479560, 23154058, 23566833, 23768953). This variant is also known as 1801delAG. ClinVar contains an entry for this variant (Variation ID: 11303). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Nov 12, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 20, 2020	A hemizygous 2 base pair deletion in exon 5 of the ABCD1 gene that results in a frameshift and premature truncation of the protein 83 amino acids downstream to codon 472 was detected. The observed variant c.1415_1416delAG (p.Gln472ArgfsTer83) has been reported previously in patients affected with adrenoleukodystrophy (Niu et al. 2013) and also classified as pathogenic in the ClinVar database. The variant has not been reported in the 1000 genomes and gnomAD databases. The reference region is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 19, 2018	This variant was identified as hemizygous -
not provided, no classification provided	literature only	GeneReviews	-	This variant has been reported in 7% of families and has been observed with approximately the same frequency in all ethnic groups. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 10, 2020	Variant summary: ABCD1 c.1415_1416delAG (p.Gln472ArgfsX83) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182139 control chromosomes. c.1415_1416delAG has been extensively reported in the literature in multiple individuals from diverse ethnic cohorts affected with Adrenoleukodystrophy. Some of the original reports of its identification are ascertained here (example, Feigenbaum_1996, Kemp_1994, Kok_1995, Ligtenberg_1995, Coll_2005, Pan_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete absence of protein expression (example, Feigenbaum_1996, Coll_2005). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011303). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8004093, 34826210, 34347682, 11748843, 8651290, 8048932, 23768953, 23962690, 23154058, 31418856, 35578252, 34946879) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	ABCD1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2020	The ABCD1 c.1415_1416delAG, p.Gln472fs variant (rs387906494) has been reported in multiple individuals diagnosed with X-linked adrenoleukodystrophy (ALD database and references therein). It is listed as pathogenic in ClinVar (Variation ID: 11303), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: ALD database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2018	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

ABCD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

The ABCD1 c.1415_1416delAG variant is predicted to result in a frameshift and premature protein termination (p.Gln472Argfs*83). This variant has been reported in multiple individuals with X-linked adrenoleukodystrophy (see, for example, Petrillo et al. 2013. PubMed ID: 23768953; Kemp et al. 2001. PubMed ID: 11748843; the ABCD1 Variant Registry at https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ABCD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs387906494; hg19: chrX-153002631;