NM_005169.4(PHOX2A):c.215C>T (p.Ala72Val) AND Fibrosis of extraocular muscles, congenital, 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 4, 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:: RCV000007242.10

Allele description [Variation Report for NM_005169.4(PHOX2A):c.215C>T (p.Ala72Val)]

NM_005169.4(PHOX2A):c.215C>T (p.Ala72Val)

Gene:

PHOX2A:paired like homeobox 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_005169.4(PHOX2A):c.215C>T (p.Ala72Val)

HGVS:

NC_000011.10:g.72243790G>A
NG_008169.1:g.5387C>T
NM_005169.3:c.215C>T
NM_005169.4:c.215C>TMANE SELECT
NP_005160.2:p.Ala72Val
NC_000011.9:g.71954834G>A
NM_005169.4:c.215C>T
O14813:p.Ala72Val

Protein change:

A72V; ALA72VAL

Links:

UniProtKB: O14813#VAR_019014; OMIM: 602753.0003; dbSNP: rs104894269

NCBI 1000 Genomes Browser:

rs104894269

Molecular consequence:

NM_005169.4:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Fibrosis of extraocular muscles, congenital, 2 (CFEOM2)
Synonyms:: FEOM2 LOCUS; FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0011181; MedGen: C1865915; OMIM: 602078

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027438	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003812866	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809573	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000027438

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2001)

germline

literature only

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

SCV003812866

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 5, 2020)

germline

clinical testing

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

SCV004809573

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 4, 2024)

germline

clinical testing

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

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC.

Nat Genet. 2001 Nov;29(3):315-20.

PubMed [citation]

PMID:: 11600883

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 OMIM, SCV000027438.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of 2 consanguineous Saudi Arabian families (BB and BD) with congenital fibrosis of extraocular muscles-2 (CFEOM2; 602078), Nakano et al. (2001) identified a homozygous C-to-T mutation at nucleotide 386 (386C-T) in exon 1 of the PHOX2A gene, resulting in an alanine-to-valine substitution at codon 72 (A72V). This mutation occurred within the brachyury-like domain, a short peptide sequence (amino acids 61 to 75) of ARIX with high homology to 'brachyury' (601397) and PAX9 (167416). The first 152 amino acids of ARIX, encompassing both the brachyury-like and homeodomain segments, are 100% identical in human, mouse, and rat orthologs, and alanine-72 is conserved between ARIX and its paralog PMX2B (also known as PHOX2B; 603851). However, the mutation could also affect splicing since it occurs at position -3 of the exon 1 splice donor sequence.

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

From Revvity Omics, Revvity, SCV003812866.2

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809573.1

#	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

Last Updated: Aug 4, 2024

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