4-41745972-AGCTGCCGCCGCTGCC-AGCTGCCGCCGCTGCCGCTGCCGCCGCTGCC

Variant names:

• chr4-41745972-A-AGCTGCCGCCGCTGCC
• rs761018157
• NM_003924.4:c.765_779dupGGCAGCGGCGGCAGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4 PP5_Very_Strong

The NM_003924.4(PHOX2B):​c.765_779dupGGCAGCGGCGGCAGC​(p.Ala256_Ala260dup) 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHOX2B NM_003924.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.633
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Haddad syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• neuroblastoma, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• congenital central hypoventilation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003924.4.
• PP5: Variant 4-41745972-A-AGCTGCCGCCGCTGCC is Pathogenic according to our data. Variant chr4-41745972-A-AGCTGCCGCCGCTGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 429242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.765_779dupGGCAGCGGCGGCAGC	p.Ala256_Ala260dup	disruptive_inframe_insertion	Exon 3 of 3	ENST00000226382.4	NP_003915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOX2B	ENST00000226382.4	c.765_779dupGGCAGCGGCGGCAGC	p.Ala256_Ala260dup	disruptive_inframe_insertion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*46_*60dupGGCAGCGGCGGCAGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1179708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 572888

African (AFR) AF: 0.00 AC: 0 AN: 25086

American (AMR) AF: 0.00 AC: 0 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18228

East Asian (EAS) AF: 0.00 AC: 0 AN: 29218

South Asian (SAS) AF: 0.00 AC: 0 AN: 34654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 972502

Other (OTH) AF: 0.00 AC: 0 AN: 47044

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital central hypoventilation Pathogenic:2

Jan 21, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous inframe insertion variant, NM_003924.3(PHOX2B):c.765_779dup, has been identified in exon 3 of 3 of the PHOX2B gene. The variant is predicted to result in an inframe insertion of 5 amino acid at position 256-260 of the protein (NM_003924.3(PHOX2B):p.(Ala256_Ala260dup)), commonly denoted p.Ala256_Ala260dup. The variant is absent in population databases (gnomAD, ExAC). Alanine repeat expansions within the polyalanine stretch of the PHOX2B gene have previously been reported in association with congenital central hypoventilation syndrome (Amiel J. et al., 2003; Matera A. et al., 2004; Serra I. et al., 2010). Analysis of parental samples indicated this variant to be de-novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Jul 27, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS2; PS4M; PM2 -

PHOX2B-related disorder Pathogenic:1

Aug 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PHOX2B c.765_779dup15 variant is predicted to result in an in-frame duplication (p.Ala256_Ala260dup). An expansion of the polyalanine repeat region from 20 repeats (normal) to 25 repeats has previously been reported to be causative for CCHS (Serra et al. 2010. PubMed ID: 20456320; Ribeiro et al. 2021. PubMed ID: 34168928; Rojnueangnit and Descartes. 2018. PubMed ID: 29531718; Falik et al. 2020. PubMed ID: 32822965). This variant is not present in a large population database (http://gnomad.broadinstitute.org) and is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000494462.1/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala241[25] pathogenic mutation, located in coding exon 3 of the PHOX2B gene, results from an expansion of the polyalanine repeat region from 20 to 25 repeats. This expansion mutation is associated with congenital central hypoventilation syndrome (Amiel J et al. Nat. Genet., 2003 Apr;33(4):459-61; Matera I et al. J. Med. Genet., 2004 May;41(5):373-80; Serra A et al. Ann. Hum. Genet., 2010 Jul;74(4):369-74; Australian Genomics Health Alliance Acute Care Flagship. JAMA 2020 06;323(24):2503-11). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=74/26	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs761018157; hg19: chr4-41747989;