NM_003924.4(PHOX2B):c.765_779dup (p.Ala256_Ala260dup) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 31, 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:: RCV000494462.4

Allele description [Variation Report for NM_003924.4(PHOX2B):c.765_779dup (p.Ala256_Ala260dup)]

NM_003924.4(PHOX2B):c.765_779dup (p.Ala256_Ala260dup)

Gene:

PHOX2B:paired like homeobox 2B [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

4p13

Genomic location:

Preferred name:

NM_003924.4(PHOX2B):c.765_779dup (p.Ala256_Ala260dup)

HGVS:

NC_000004.12:g.41745984_41745998dup
NG_008243.1:g.7984_7998dup
NG_053075.1:g.110_124dup
NM_003924.3:c.765_779dup15
NM_003924.4:c.765_779dupMANE SELECT
NP_003915.2:p.Ala256_Ala260dup
NP_003915.2:p.Ala256_Ala260dup
LRG_513t1:c.765_779dup
LRG_513:g.7984_7998dup
LRG_513p1:p.Ala256_Ala260dup
NC_000004.11:g.41748001_41748015dup
NM_003924.3:c.765_779dup
NM_003924.3:c.765_779dup15
NM_003924.3:c.765_779dupGGCAGCGGCGGCAGC

Links:

dbSNP: rs761018157

NCBI 1000 Genomes Browser:

rs761018157

Molecular consequence:

NM_003924.4:c.765_779dup - inframe_insertion - [Sequence Ontology: SO:0001821]

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
SCV000581758	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 31, 2023)	germline	clinical testing	Citation Link,
SCV005199395	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	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

SCV000581758

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 31, 2023)

germline

clinical testing

Citation Link,

SCV005199395

Clinical Genetics Laboratory, Skane University Hospital Lund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 13, 2022)

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 GeneDx, SCV000581758.6

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

Description

Duplication of 5 alanine residues in the second polyalanine tract, resulting in a total of 25 alanine residues; Polyalanine repeat expansion of 24 and 25 repeats have been identified in individuals with variable age of onset and phenotypes, ranging from asymptomatic/mild presentations to newborns with congenital central hypoventilation syndrome (PMID: 20301600; 22125732, 23460419, 18798833); De novo variant with confirmed parentage in a patient previously tested at GeneDx and as an apparently de novo variant in multiple patients in the published literature with CCHS (PMID: 12640453); Published functional evidence indicate that expanded PHOX2B protein forms ubiquitin positive inclusions, which sequester wild-type PHOX2B, resulting in reduced transcriptional and binding activity of wild-type protein and possibly supporting a dominant-negative effect (PMID 22307522; 23103552); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12640453, 34168928, 15121777, 32573669, 15860752, 20456320, 22307522, 20301600, 22125732, 23460419, 18798833)

#	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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199395.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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