NM_003924.4(PHOX2B):c.56C>G (p.Ala19Gly) AND Haddad syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 10, 2023
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:: RCV002231822.12

Allele description [Variation Report for NM_003924.4(PHOX2B):c.56C>G (p.Ala19Gly)]

NM_003924.4(PHOX2B):c.56C>G (p.Ala19Gly)

Genes:

PHOX2B-AS1:PHOX2B antisense RNA 1 [Gene - HGNC]
PHOX2B:paired like homeobox 2B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p13

Genomic location:

Preferred name:

NM_003924.4(PHOX2B):c.56C>G (p.Ala19Gly)

HGVS:

NC_000004.12:g.41748555G>C
NG_008243.1:g.5416C>G
NM_003924.4:c.56C>GMANE SELECT
NP_003915.2:p.Ala19Gly
NP_003915.2:p.Ala19Gly
LRG_513t1:c.56C>G
LRG_513:g.5416C>G
LRG_513p1:p.Ala19Gly
NC_000004.11:g.41750572G>C
NM_003924.3:c.56C>G

Protein change:

A19G

Links:

dbSNP: rs1353983410

NCBI 1000 Genomes Browser:

rs1353983410

Molecular consequence:

NM_003924.4:c.56C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Haddad syndrome (OHD)
Synonyms:: Ondine-Hirschsprung disease
Identifiers:: MONDO: MONDO:0020493; MedGen: C1859049; Orphanet: 99803

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000644036	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33958749, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000644036

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 10, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).

Zhou A, Rand CM, Hockney SM, Niewijk G, Reineke P, Speare V, Berry-Kravis EM, Zhou L, Jennings LJ, Yu M, Ceccherini I, Bachetti T, Pennock M, Yap KL, Weese-Mayer DE.

Genet Med. 2021 Sep;23(9):1656-1663. doi: 10.1038/s41436-021-01178-x. Epub 2021 May 6.

PubMed [citation]

PMID:: 33958749

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644036.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 467731). This missense change has been observed in individual(s) with clinical features of PHOX2B-related conditions (PMID: 33958749). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 19 of the PHOX2B protein (p.Ala19Gly).

#	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: Nov 24, 2024

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