NM_000033.4(ABCD1):c.892G>A (p.Gly298Ser) AND Adrenoleukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jun 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000824100.2

Allele description [Variation Report for NM_000033.4(ABCD1):c.892G>A (p.Gly298Ser)]

NM_000033.4(ABCD1):c.892G>A (p.Gly298Ser)

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.892G>A (p.Gly298Ser)
HGVS:
  • NC_000023.11:g.153726158G>A
  • NG_009022.2:g.6291G>A
  • NG_023231.1:g.3589C>T
  • NM_000033.4:c.892G>AMANE SELECT
  • NP_000024.2:p.Gly298Ser
  • LRG_1017t1:c.892G>A
  • LRG_1017:g.6291G>A
  • LRG_1017p1:p.Gly298Ser
  • NC_000023.10:g.152991613G>A
  • NM_000033.3:c.892G>A
Protein change:
G298S
Links:
dbSNP: rs1603232243
NCBI 1000 Genomes Browser:
rs1603232243
Molecular consequence:
  • NM_000033.4:c.892G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000964982Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 30, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000992377Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Uncertain significance
(Jun 10, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset.

Wichers M, Köhler W, Brennemann W, Boese V, Sokolowski P, Bidlingmaier F, Ludwig M.

Hum Genet. 1999 Jul-Aug;105(1-2):116-9.

PubMed [citation]
PMID:
10480364

Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.

Lachtermacher MB, Seuánez HN, Moser AB, Moser HW, Smith KD.

Hum Mutat. 2000;15(4):348-53.

PubMed [citation]
PMID:
10737980
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000964982.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glycine with serine at codon 298 of the ABCD1 protein (p.Gly298Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ABCD1-related conditions (PMID: 10737980, Invitae). 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. The observation of additional missense substitutions at this codon (p.Gly298Asp and p.Gly298Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 10480364, 26454440). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV000992377.1

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

Last Updated: Feb 27, 2021

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