NM_000033.4(ABCD1):c.761C>T (p.Thr254Met) AND Adrenoleukodystrophy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 10, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000633477.4

Allele description [Variation Report for NM_000033.4(ABCD1):c.761C>T (p.Thr254Met)]

NM_000033.4(ABCD1):c.761C>T (p.Thr254Met)

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.761C>T (p.Thr254Met)
HGVS:
  • NC_000023.11:g.153726027C>T
  • NG_009022.2:g.6160C>T
  • NG_023231.1:g.3720G>A
  • NM_000033.4:c.761C>TMANE SELECT
  • NP_000024.2:p.Thr254Met
  • LRG_1017t1:c.761C>T
  • LRG_1017:g.6160C>T
  • LRG_1017p1:p.Thr254Met
  • NC_000023.10:g.152991482C>T
  • NM_000033.3:c.761C>T
Protein change:
T254M
Links:
dbSNP: rs1131691743
NCBI 1000 Genomes Browser:
rs1131691743
Molecular consequence:
  • NM_000033.4:c.761C>T - 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
SCV000754709Invitaecriteria provided, single submitter
Pathogenic
(May 10, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001440567Institute of Human Genetics, University of Leipzig Medical Centercriteria provided, single submitter
Likely pathogenic
(Jan 1, 2019)
unknownclinical 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
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy.

Krasemann EW, Meier V, Korenke GC, Hunneman DH, Hanefeld F.

Hum Genet. 1996 Feb;97(2):194-7.

PubMed [citation]
PMID:
8566952

Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.

Horn MA, Retterstøl L, Abdelnoor M, Skjeldal OH, Tallaksen CM.

Pediatr Neurol. 2013 Mar;48(3):212-9. doi: 10.1016/j.pediatrneurol.2012.12.007.

PubMed [citation]
PMID:
23419472
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000754709.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces threonine with methionine at codon 254 of the ABCD1 protein (p.Thr254Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as de novo in two independent individuals affected with adrenoleukodystrophy and in a Norwegian kindred with the same condition (PMID: 8566952, 23419472, Invitae). ClinVar contains an entry for this variant (Variation ID: 430026). 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. For these reasons, this variant has been classified as Pathogenic.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440567.1

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

Last Updated: May 10, 2021

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