NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup) AND Congenital central hypoventilation

Germline classification:: Pathogenic (1 submission)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003335452.1

Allele description [Variation Report for NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup)]

NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup)

Genes:

PHOX2B:paired like homeobox 2B [Gene - OMIM - HGNC]
LOC110011216:paired like homeobox 2b polyalanine repeat instability region [Gene]

Variant type:

Duplication

Cytogenetic location:

4p13

Genomic location:

Preferred name:

NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup)

HGVS:

NC_000004.12:g.41745990_41746010dup
NG_008243.1:g.7975_7995dup
NG_053075.1:g.116_136dup
NM_003924.4:c.756_776dupMANE SELECT
NP_003915.2:p.Ala254_Ala260dup
NP_003915.2:p.Ala254_Ala260dup
LRG_513t1:c.756_776dup
LRG_513:g.7975_7995dup
LRG_513p1:p.Ala254_Ala260dup
NC_000004.11:g.41748007_41748027dup
NM_003924.3:c.756_776dup
NM_003924.3:c.756_776dupGGCGGCAGCGGCAGCGGCGGC

Links:

dbSNP: rs17879189

NCBI 1000 Genomes Browser:

rs17879189

Molecular consequence:

NM_003924.4:c.756_776dup - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Name:: Congenital central hypoventilation
Synonyms:: Idiopathic congenital central alveolar hypoventilation; Congenital failure of autonomic control; Primary alveolar hypoventilation; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0800031; MedGen: C1275808; Orphanet: 661; Orphanet: 99803; OMIM: PS209880

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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046366	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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

SCV004046366

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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	yes	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046366.1

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

Description

This variant is located within the polyalanine tract in exon 3 of the PHOX2B gene and causes an in-frame duplication resulting in an expansion event. An alternative nomenclature for this variant is p.Ala241[27], which corresponds to a 27 polyalanine repeat expansion (PMID: 20301600). Repeat expansions within the polyalanine tract in the PHOX2B gene are an established mechanism of disease and have been previously reported in patients with Congenital Central Hypoventilation Syndrome (PMID: 12640453, 14566559, 14608649, 15121777). This variant has been previously reported as a heterozygous change in multiple individuals with Congenital Central Hypoventilation Syndrome (PMID: 20456320). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating that this variant likely occurred as a de novo event. Based on the available evidence, the c.756_776dup (p.Ala254_Ala260dup) variant is classified as Pathogenic.

#	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: Oct 13, 2024

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