NM_000033.4(ABCD1):c.838C>T (p.Arg280Cys) AND not provided

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 16, 2023
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:: RCV001781320.16

Allele description [Variation Report for NM_000033.4(ABCD1):c.838C>T (p.Arg280Cys)]

NM_000033.4(ABCD1):c.838C>T (p.Arg280Cys)

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.838C>T (p.Arg280Cys)

HGVS:

NC_000023.11:g.153726104C>T
NG_009022.2:g.6237C>T
NG_023231.1:g.3643G>A
NM_000033.4:c.838C>TMANE SELECT
NP_000024.2:p.Arg280Cys
LRG_1017t1:c.838C>T
LRG_1017:g.6237C>T
LRG_1017p1:p.Arg280Cys
NC_000023.10:g.152991559C>T
NM_000033.3:c.838C>T
P33897:p.Arg280Cys

Protein change:

R280C

Links:

UniProtKB: P33897#VAR_013347; dbSNP: rs193922098

NCBI 1000 Genomes Browser:

rs193922098

Molecular consequence:

NM_000033.4:c.838C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001474333	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jun 18, 2020)	germline	clinical testing	Citation Link,
SCV002023955	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004028109	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 16, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001474333

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Jun 18, 2020)

germline

clinical testing

Citation Link,

SCV002023955

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 25, 2022)

germline

clinical testing

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

SCV004028109

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Aug 16, 2023)

germline

clinical testing

Citation Link

Help

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

Citations

PubMed

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474333.1

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

Description

The ABCD1 c.838C>T; p.Arg280Cys variant (rs193922098) is reported in several individuals with X-linked adrenoleukodystrophy and increased very-long-chain fatty acids (see link to ABCD1 variant database, Coll 2005, Isaacs 2014). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 35643) and is reported in the general population in 2 out of 128,935 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 280 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Link to ABCD1 database: https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1 Coll MJ et al. X-linked Adrenoleukodystrophy in Spain. Identification of 26 Novel Mutations in the ABCD1 Gene in 80 Patients. Improvement of Genetic Counseling in 162 Relative Females. Clin Genet. 2005 May;67(5):418-24. Isaacs D et al. Adult-onset Adrenoleukodystrophy Presenting After Chemotherapy: No Black and White Matter. Neurol Clin Pract. 2014 Apr;4(2):168-170.

#	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 Revvity Omics, Revvity, SCV002023955.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV004028109.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29443243, 11748843, 33920672, 35466195, 35076462, 36076658, 15811009)

#	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

Last Updated: Nov 24, 2024

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