VCV000368044.71 - ClinVar

NM_000033.4(ABCD1):c.38A>C (p.Asn13Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000033.4(ABCD1):c.38A>C (p.Asn13Thr)

Variation ID: 368044 Accession: VCV000368044.71

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 153725304 (GRCh38) [ NCBI UCSC ] X: 152990759 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	May 1, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000033.4:c.38A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000024.2:p.Asn13Thr	missense
NC_000023.11:g.153725304A>C
NC_000023.10:g.152990759A>C
NG_009022.2:g.5437A>C
NG_023231.1:g.4443T>G
LRG_1017:g.5437A>C
LRG_1017t1:c.38A>C	LRG_1017p1:p.Asn13Thr
	P33897:p.Asn13Thr

... more HGVS ... less HGVS

Protein change

N13T

Other names

Canonical SPDI

NC_000023.11:153725303:A:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00079 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00034

1000 Genomes Project 30x 0.00062

1000 Genomes Project 0.00079

Exome Aggregation Consortium (ExAC) 0.00114

Trans-Omics for Precision Medicine (TOPMed) 0.00117

The Genome Aggregation Database (gnomAD), exomes 0.00203

The Genome Aggregation Database (gnomAD) 0.00235

Links

ClinGen: CA10549898 UniProtKB: P33897#VAR_013340 dbSNP: rs183021839 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1529	1775

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adrenoleukodystrophy	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000377597.26
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV001000486.16
not provided	Likely benign (5)	criteria provided, single submitter	Apr 13, 2021	RCV001528897.14
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Dec 9, 2016	RCV002314110.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Adrenoleukodystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000481963.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 23430809‚ 16949688‚ 11438993 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Adrenoleukodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000630006.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (Dec 09, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848238.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Nov 14, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157368.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020
Likely benign (Apr 13, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001774112.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021
Benign (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenoleukodystrophy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002045852.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022
Benign (Jan 11, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004804372.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 11438993 Comment: Variant summary: ABCD1 c.38A>C (p.Asn13Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: ABCD1 c.38A>C (p.Asn13Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1146578 control chromosomes in the gnomAD database (v4), including 979 hemizygotes and 6 homozygotes, strongly suggesting the variant is a benign polymorphism. To our knowledge, no occurrences of c.38A>C with strong evidence for causality have been reported in individuals affected with Adrenoleukodystrophy. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Dvorakova_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11438993). ClinVar contains an entry for this variant (Variation ID: 368044). Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798823.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741427.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922480.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968552.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: ABCD1 c.38A>C (p.Asn13Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1146578 control chromosomes in the gnomAD database (v4), including 979 hemizygotes and 6 homozygotes, strongly suggesting the variant is a benign polymorphism. To our knowledge, no occurrences of c.38A>C with strong evidence for causality have been reported in individuals affected with Adrenoleukodystrophy. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Dvorakova_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11438993). ClinVar contains an entry for this variant (Variation ID: 368044). Based on the evidence outlined above, the variant was classified as benign.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Novel Double Mutation in the ABCD1 Gene in a Patient with X-linked Adrenoleukodystrophy: Analysis of the Stability and Function of the Mutant ABCD1 Protein.	Morita M	JIMD reports	2013	PMID: 23430809
X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects.	Berger J	Biochimica et biophysica acta	2006	PMID: 16949688
Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange.	Dvoráková L	Human mutation	2001	PMID: 11438993

Text-mined citations for rs183021839 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000033.4(ABCD1):c.38A>C (p.Asn13Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs183021839 ...