4-41745993-CGCCGCCGCCGCTGCCGCG-CGCCGCCGCCGCTGCCGCGGCCGCCGCCGCTGCCGCG

Position:

• chr4-41745993-CGCCGCCGCCGCTGCCGCG-CGCCGCCGCCGCTGCCGCGGCCGCCGCCGCTGCCGCG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_003924.4(PHOX2B):​c.741_758dupCGCGGCAGCGGCGGCGGC​(p.Ala248_Ala253dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B NM_003924.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.14

Genes affected

PHOX2B (HGNC:9143): (paired like homeobox 2B) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome. [provided by RefSeq, Jul 2016]

PHOX2B (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-41745993-C-CGCCGCCGCCGCTGCCGCG is Pathogenic according to our data. Variant chr4-41745993-C-CGCCGCCGCCGCTGCCGCG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_003924.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.741_758dupCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253dup	disruptive_inframe_insertion	3/3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.741_758dupCGCGGCAGCGGCGGCGGC	p.Ala248_Ala253dup	disruptive_inframe_insertion	3/3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*22_*39dupCGCGGCAGCGGCGGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Aug 22, 2024	Combined evidence strength is Very Strong (score = 9).Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars. Supporting: LOVD classifies this variant as Pathogenic (PP5).Hot-spot of length 27 amino-acids has 108 missense/in-frame variants (26 pathogenic variants, 68 uncertain variants and 14 benign variants), which qualifies as strong pathogeniC (PM1). Variant not found in gnomAD genomes, Variant not found in gnomAD exomes (PM2). The position is not conserved (phyloP = 2.98 is between 1.08 and 3.58). No other in-silico engine is available (BP4). We identified this variant in a 7-year-old child with epilepsy syndrome. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Nov 29, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2023	Duplication of 6 alanine residues in the second polyalanine tract, resulting in a total of 26 alanine residues; Polyalanine repeat expansion of 26 or more repeats have been reported in association with congenital central hypoventilation syndrome (PMID: 20301600; 20208042); Observed as a de novo variant with confirmed parentage and as an apparently de novo variant in patients with CCHS tested at GeneDx and in the published literature (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: 20456320, 30850150, 12640453, 15860752, 20301600, 20208042, 22307522) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2022

The p.Ala241[26] pathogenic mutation, located in coding exon 3 of the PHOX2B gene, results from an expansion of the polyalanine repeat region from 20 to 26 repeats. This expansion mutation is associated with congenital central hypoventilation syndrome (Amiel J et al. Nat. Genet., 2003 Apr;33:459-61; Matera I et al. J. Med. Genet., 2004 May;41:373-80; Woo HY et al. J. Pediatr. Surg. 2020 Mar;55(3):387-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771383153; hg19: chr4-41748010;