NM_000033.4(ABCD1):c.508G>A (p.Ala170Thr) AND Adrenoleukodystrophy

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 6, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000798341.14

Allele description [Variation Report for NM_000033.4(ABCD1):c.508G>A (p.Ala170Thr)]

NM_000033.4(ABCD1):c.508G>A (p.Ala170Thr)

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.508G>A (p.Ala170Thr)

HGVS:

NC_000023.11:g.153725774G>A
NG_009022.2:g.5907G>A
NG_023231.1:g.3973C>T
NM_000033.4:c.508G>AMANE SELECT
NP_000024.2:p.Ala170Thr
LRG_1017t1:c.508G>A
LRG_1017:g.5907G>A
LRG_1017p1:p.Ala170Thr
NC_000023.10:g.152991229G>A
NM_000033.3:c.508G>A
p.Ala170Thr

Protein change:

A170T

Links:

dbSNP: rs782293513

NCBI 1000 Genomes Browser:

rs782293513

Molecular consequence:

NM_000033.4:c.508G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000937954	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31074578, 28492532
SCV001477505	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045714	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060055	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 16, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000937954.6

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 170 of the ABCD1 protein (p.Ala170Thr). This variant is present in population databases (rs782293513, gnomAD 0.001%). This missense change has been observed in individual(s) with ABCD1-related conditions (PMID: 31074578; Invitae). ClinVar contains an entry for this variant (Variation ID: 644432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCD1 protein function. 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.

#	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

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV001477505.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002045714.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060055.2

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

Description

NM_000033.3(ABCD1):c.508G>A(A170T) is a missense variant classified as a variant of uncertain significance in the context of X-linked adrenoleukodystrophy. A170T has been observed in cases with relevant disease (PMID: 31074578). Functional assessments of this variant are not available in the literature. A170T has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_000033.3(ABCD1):c.508G>A(A170T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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