NM_003924.4(PHOX2B):c.691G>A (p.Gly231Ser) AND Haddad syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 21, 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:: RCV001214365.8

Allele description [Variation Report for NM_003924.4(PHOX2B):c.691G>A (p.Gly231Ser)]

NM_003924.4(PHOX2B):c.691G>A (p.Gly231Ser)

Gene:

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.691G>A (p.Gly231Ser)

HGVS:

NC_000004.12:g.41746061C>T
NG_008243.1:g.7910G>A
NG_053075.1:g.187C>T
NM_003924.4:c.691G>AMANE SELECT
NP_003915.2:p.Gly231Ser
LRG_513t1:c.691G>A
LRG_513:g.7910G>A
NC_000004.11:g.41748078C>T
NM_003924.3:c.691G>A

Protein change:

G231S

Links:

dbSNP: rs1577559082

NCBI 1000 Genomes Browser:

rs1577559082

Molecular consequence:

NM_003924.4:c.691G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Homo sapiens scavenger receptor class F member 1 (SCARF1), transcript variant 3,...
Homo sapiens scavenger receptor class F member 1 (SCARF1), transcript variant 3, mRNA
gi|1676338018|ref|NM_145350.3|

Nucleotide
UI-CF-EC1-acd-l-20-0-UI.s1 UI-CF-EC1 Homo sapiens cDNA clone UI-CF-EC1-acd-l-20-...
UI-CF-EC1-acd-l-20-0-UI.s1 UI-CF-EC1 Homo sapiens cDNA clone UI-CF-EC1-acd-l-20-0-UI 3', mRNA sequence
gi|19592577|gnl|dbEST|11793284|gb|B 86.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001386042	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 21, 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

SCV001386042

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 21, 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, SCV001386042.5

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

Description

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 231 of the PHOX2B protein (p.Gly231Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with later-onset hypoventilation with hypothalamic dysfunction (PMID: 33958749). ClinVar contains an entry for this variant (Variation ID: 826705).

#	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 8, 2024

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