NM_139058.3(ARX):c.1561G>A (p.Ala521Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 30, 2024
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:: RCV000193135.8

Allele description [Variation Report for NM_139058.3(ARX):c.1561G>A (p.Ala521Thr)]

NM_139058.3(ARX):c.1561G>A (p.Ala521Thr)

Gene:

ARX:aristaless related homeobox [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp21.3

Genomic location:

Preferred name:

NM_139058.3(ARX):c.1561G>A (p.Ala521Thr)

HGVS:

NC_000023.11:g.25004798C>T
NG_008281.1:g.16151G>A
NM_139058.3:c.1561G>AMANE SELECT
NP_620689.1:p.Ala521Thr
NC_000023.10:g.25022915C>T
NM_139058.2:c.1561G>A
Q96QS3:p.Ala521Thr

Protein change:

A521T

Links:

UniProtKB: Q96QS3#VAR_033263; dbSNP: rs746120093

NCBI 1000 Genomes Browser:

rs746120093

Molecular consequence:

NM_139058.3:c.1561G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000246554	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Uncertain significance (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005380975	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000246554

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2007)

Uncertain significance
(Feb 8, 2013)

germline

clinical testing

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

SCV005380975

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 30, 2024)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

Kato M, Das S, Petras K, Kitamura K, Morohashi KI, Abuelo DN, Barr M, Bonneau D, Brady AF, Carpenter NJ, Cipero KL, Frisone F, Fukuda T, Guerrini R, Iida E, Itoh M, Lewanda AF, Nanba Y, Oka A, Proud VK, Saugier-Veber P, Schelley SL, et al.

Hum Mutat. 2004 Feb;23(2):147-159. doi: 10.1002/humu.10310.

PubMed [citation]

PMID:: 14722918

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000246554.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005380975.1

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

Description

Variant summary: ARX c.1561G>A (p.Ala521Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 111006 control chromosomes, including one hemizygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1561G>A has been reported in the literature in an individual affected with X-linked lissencephaly with abnormal genitalia and cerebellar hypoplasia (Kato_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 14722918). ClinVar contains an entry for this variant (Variation ID: 210322). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Oct 26, 2024

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