NM_000033.4(ABCD1):c.1552C>G (p.Arg518Gly) AND Adrenoleukodystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000633480.6

Allele description [Variation Report for NM_000033.4(ABCD1):c.1552C>G (p.Arg518Gly)]

NM_000033.4(ABCD1):c.1552C>G (p.Arg518Gly)

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.1552C>G (p.Arg518Gly)

HGVS:

NC_000023.11:g.153740155C>G
NG_009022.2:g.20288C>G
NM_000033.4:c.1552C>GMANE SELECT
NP_000024.2:p.Arg518Gly
LRG_1017t1:c.1552C>G
LRG_1017:g.20288C>G
LRG_1017p1:p.Arg518Gly
NC_000023.10:g.153005609C>G
NM_000033.3:c.1552C>G

Protein change:

R518G

Links:

dbSNP: rs128624224

NCBI 1000 Genomes Browser:

rs128624224

Molecular consequence:

NM_000033.4:c.1552C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000754712	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21068741, 20195870, 8040304, 27084228, 14767898, 16415970, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000754712

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 8, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan.

Shimozawa N, Honda A, Kajiwara N, Kozawa S, Nagase T, Takemoto Y, Suzuki Y.

J Hum Genet. 2011 Feb;56(2):106-9. doi: 10.1038/jhg.2010.139. Epub 2010 Nov 11. Review.

PubMed [citation]

PMID:: 21068741

Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy.

Guettsches AK, Kuechler A, Gal A, Schmitz W, Tegenthoff M, Vorgerd M.

J Neurol. 2010 Aug;257(8):1394-5. doi: 10.1007/s00415-010-5505-8. Epub 2010 Mar 2. Erratum in: J Neurol. 2010 Aug;257(8):1417.

PubMed [citation]

PMID:: 20195870

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000754712.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Arg518Gln, p.Arg518Trp, p.Arg518Pro) have been reported in several individuals affected with adrenoleukodystrophy (PMID: 21068741, 20195870, 8040304, 27084228). This suggests that the arginine residue is critical for ABCD1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in several individuals affected with adrenoleukodystrophy¬† (PMID: 14767898, 16415970). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 518 of the ABCD1 protein (p.Arg518Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.

#	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

Last Updated: Feb 20, 2024

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