NM_000033.4(ABCD1):c.1165C>T (p.Arg389Cys) AND Adrenoleukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000761215.3

Allele description [Variation Report for NM_000033.4(ABCD1):c.1165C>T (p.Arg389Cys)]

NM_000033.4(ABCD1):c.1165C>T (p.Arg389Cys)

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.1165C>T (p.Arg389Cys)
HGVS:
  • NC_000023.11:g.153736195C>T
  • NG_009022.2:g.16328C>T
  • NM_000033.4:c.1165C>TMANE SELECT
  • NP_000024.2:p.Arg389Cys
  • LRG_1017t1:c.1165C>T
  • LRG_1017:g.16328C>T
  • LRG_1017p1:p.Arg389Cys
  • NC_000023.10:g.153001649C>T
  • NM_000033.3:c.1165C>T
Protein change:
R389C
Links:
dbSNP: rs128624215
NCBI 1000 Genomes Browser:
rs128624215
Molecular consequence:
  • NM_000033.4:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000891169Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesotacriteria provided, single submitter
Likely pathogenic
(Apr 17, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001418216Invitaecriteria provided, single submitter
Uncertain significance
(Sep 20, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy.

Asheuer M, Bieche I, Laurendeau I, Moser A, Hainque B, Vidaud M, Aubourg P.

Hum Mol Genet. 2005 May 15;14(10):1293-303. Epub 2005 Mar 30.

PubMed [citation]
PMID:
15800013
See all PubMed Citations (8)

Details of each submission

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891169.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Invitae, SCV001418216.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with cysteine at codon 389 of the ABCD1 protein (p.Arg389Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with adrenoleukodystrophy as well as in an individual with hereditary spastic paraplegia (PMID: 15800013, 22280810, 30564185). ClinVar contains an entry for this variant (Variation ID: 623115). 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 disrupts the p.Arg389 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8566952, 7825602, 16401743). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 12, 2021

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