NM_000033.4(ABCD1):c.442A>G (p.Asn148Asp) AND Adrenoleukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 13, 2022
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:: RCV001069371.8

Allele description [Variation Report for NM_000033.4(ABCD1):c.442A>G (p.Asn148Asp)]

NM_000033.4(ABCD1):c.442A>G (p.Asn148Asp)

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.442A>G (p.Asn148Asp)

HGVS:

NC_000023.11:g.153725708A>G
NG_009022.2:g.5841A>G
NG_023231.1:g.4039T>C
NM_000033.4:c.442A>GMANE SELECT
NP_000024.2:p.Asn148Asp
LRG_1017t1:c.442A>G
LRG_1017:g.5841A>G
LRG_1017p1:p.Asn148Asp
NC_000023.10:g.152991163A>G
NM_000033.3:c.442A>G

Protein change:

N148D

Links:

dbSNP: rs1557052362

NCBI 1000 Genomes Browser:

rs1557052362

Molecular consequence:

NM_000033.4:c.442A>G - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234535	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 12, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7849723, 10190819, 10480364, 15811009, 20800589, 28492532
SCV002580906	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 13, 2022)	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

SCV001234535

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 12, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002580906

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 13, 2022)

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	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD).

Fuchs S, Sarde CO, Wedemann H, Schwinger E, Mandel JL, Gal A.

Hum Mol Genet. 1994 Oct;3(10):1903-5. No abstract available.

PubMed [citation]

PMID:: 7849723

Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.

Takano H, Koike R, Onodera O, Sasaki R, Tsuji S.

Arch Neurol. 1999 Mar;56(3):295-300.

PubMed [citation]

PMID:: 10190819

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001234535.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn148 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7849723, 10190819, 10480364, 15811009; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 862617). This missense change has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 20800589; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 148 of the ABCD1 protein (p.Asn148Asp).

#	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 MGZ Medical Genetics Center, SCV002580906.1

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

#	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		2	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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