NM_000033.4(ABCD1):c.1224G>A (p.Glu408=) AND Adrenoleukodystrophy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001970107.7

Allele description [Variation Report for NM_000033.4(ABCD1):c.1224G>A (p.Glu408=)]

NM_000033.4(ABCD1):c.1224G>A (p.Glu408=)

Gene:

ABCD1:ATP binding cassette subfamily D member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000033.4(ABCD1):c.1224G>A (p.Glu408=)

HGVS:

NC_000023.11:g.153736254G>A
NG_009022.2:g.16387G>A
NM_000033.4:c.1224G>AMANE SELECT
NP_000024.2:p.Glu408=
LRG_1017t1:c.1224G>A
LRG_1017:g.16387G>A
LRG_1017p1:p.Glu408=
NC_000023.10:g.153001708G>A

Links:

dbSNP: rs2148395507

NCBI 1000 Genomes Browser:

rs2148395507

Molecular consequence:

NM_000033.4:c.1224G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Name:: Adrenoleukodystrophy (ALD)
Synonyms:: ADDISON DISEASE AND CEREBRAL SCLEROSIS; BRONZE SCHILDER DISEASE; MELANODERMIC LEUKODYSTROPHY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018544; MedGen: C0162309; OMIM: 300100

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aspartyl protease family protein 1 [Cucumis sativus]
aspartyl protease family protein 1 [Cucumis sativus]
gi|449434470|ref|XP_004135019.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002236799	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 7581394, 30069915, 28492532
SCV004232350	Oleksyk Lab, Oakland University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002236799

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004232350

Oleksyk Lab, Oakland University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Ukrainian	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002236799.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1455740). This variant has been observed in individual(s) with ABCD1-related conditions (PMID: 7581394, 30069915; Invitae). In at least one individual the variant was observed to be de novo. This sequence change affects codon 408 of the ABCD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCD1 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Oleksyk Lab, Oakland University, SCV004232350.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Ukrainian	1	not provided	not provided	clinical testing	PubMed (1)
2	Ukrainian	1	not provided	not provided	clinical testing	PubMed (1)
3	Ukrainian	1	not provided	not provided	clinical testing	PubMed (1)

Description

Patient had elevated VLCFA

The patient had elevated VLCFA

Description

Splice site variant in exon 3 of ABCD1 gene (c.1224G > A, Glu408 =) caused highly similar AMN phenotype with cerebral involvement (cALD) in adulthood in two brothers, both had adrenal insufficiency from childhood.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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