NM_000033.4(ABCD1):c.1366dup (p.Arg456fs) AND Adrenoleukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 28, 2021
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:: RCV000029284.5

Allele description [Variation Report for NM_000033.4(ABCD1):c.1366dup (p.Arg456fs)]

NM_000033.4(ABCD1):c.1366dup (p.Arg456fs)

Gene:

ABCD1:ATP binding cassette subfamily D member 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000033.4(ABCD1):c.1366dup (p.Arg456fs)

HGVS:

NC_000023.11:g.153736486dup
NG_009022.2:g.16619dup
NM_000033.4:c.1366dupMANE SELECT
NP_000024.2:p.Arg456fs
LRG_1017t1:c.1366dup
LRG_1017:g.16619dup
LRG_1017p1:p.Arg456fs
NC_000023.10:g.153001938_153001939insC
NC_000023.10:g.153001940dup
NM_000033.3:c.1366dupC
p.Arg456ProfsX100

Protein change:

R456fs

Links:

dbSNP: rs193922093

NCBI 1000 Genomes Browser:

rs193922093

Molecular consequence:

NM_000033.4:c.1366dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000051930	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation, clinical testing	Citation Link,
SCV002229261	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11748843, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000051930

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

likely pathogenic
(Aug 18, 2011)

germline

curation, clinical testing

Citation Link,

SCV002229261

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 28, 2021)

germline

clinical testing

PubMed (2)
[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	yes	1	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.

Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW.

Hum Mutat. 2001 Dec;18(6):499-515. Review.

PubMed [citation]

PMID:: 11748843

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000051930.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided
2	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 2

Co-occurrences

#	Zygosity	Alleles	Number of Observations
2	SingleHeterozygote	ABCD1:c.2246G>C	1

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002229261.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with ABCD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 35637). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg456Profs*100) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843).

#	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: Sep 29, 2024

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