4-41745984-TGCCGCTGCCGCCGCC-TGCCGCTGCCGCCGCCGCCGCTGCCGCCGCC

Variant names:

• chr4-41745984-T-TGCCGCTGCCGCCGCC
• rs779557320
• NM_003924.4:c.753_767dupGGCGGCGGCAGCGGC

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.753_767dupGGCGGCGGCAGCGGC​(p.Ala252_Ala256dup) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHOX2B NM_003924.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-41745984-T-TGCCGCTGCCGCCGCC is Pathogenic according to our data. Variant chr4-41745984-T-TGCCGCTGCCGCCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 505021.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 rank	MANE	Protein	UniProt
PHOX2B	NM_003924.4	c.753_767dupGGCGGCGGCAGCGGC	p.Ala252_Ala256dup	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.753_767dupGGCGGCGGCAGCGGC	p.Ala252_Ala256dup	disruptive_inframe_insertion	Exon 3 of 3	1	NM_003924.4	ENSP00000226382.2
PHOX2B	ENST00000510424.2	n.*34_*48dupGGCGGCGGCAGCGGC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jun 21, 2024

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); 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); Observed in individuals with congenital central hypoventilation syndrome referred for genetic tested at GeneDx and in published literature (PMID: 29531718); De novo variant with confirmed parentage in multiple patients with clinical features of congenital central hypoventilation syndrome referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15121777, 14566559, 14608649, 20301600, 22125732, 23460419, 18798833, 26063465, 12640453, 15334515, 38585811, 29531718, 22307522) -

Dec 23, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 12, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ala256_Ala260dup variant in PHOX2B was identified by our study in one individual with Marcus Gunn jaw-winking synkinesis with congenital ptosis, central hypoventilation, and Hirschsprung disease, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio genome analysis showed this variant to be de novo. We believe this is a possible phenotype expansion for congenital central hypoventilation syndrome-1 with or without Hirschsprung disease. The p.Ala256_Ala260dup variant in PHOX2B has been previously reported in over 100 individuals with congenital central hypoventilation syndrome 1 with or without Hirschsprung disease (PMID: 22437207, PMID: 26063465, PMID: 14608649, PMID: 29531718, PMID: 15121777, PMID: 14566559, PMID: 15334515, PMID: 12640453, SCV001244958.1, SCV001792209.1) and segregated with disease in at least 8 affected relatives from 5 families (PMID: 22437207, PMID: 14608649). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in at least 10 individuals with confirmed paternity and maternity (PMID: 15121777, PMID: 15334515, PMID: 12640453, SCV001244958.1, SCV001792209.1) and is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 29531718). This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 505021, 429242, 988333) and has been interpreted as pathogenic by Ambry Genetics and Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital central hypoventilation syndrome-1 with or without Hirschsprung disease. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM2_Supporting, PP1_Strong (Richards 2015). -

Neuroblastoma, susceptibility to, 2;C5562075:Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4+PS3+PM4+PM2_Supporting+PP4 -

PHOX2B-related disorder Pathogenic:1

Mar 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PHOX2B c.753_767dup15 variant is predicted to result in an in-frame duplication (p.Ala256_Ala260dup). The p.Ala256_Ala260dup variant has previously been reported in multiple individuals with congenital central hypoventilation syndrome (CCHS) (Serra et al. 2010. PubMed ID: 20456320). This duplication causes an expansion of the polyalanine repeat region from 20 repeats (normal) to 25 repeats; repeat-expansions of similar size have been documented to be causative for CCHS (Matera et al. 2004. PubMed ID: 15121777). This variant is not present in a large population database (https://gnomad.broadinstitute.org/) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/505021/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 07, 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;33:459-61; Matera I et al. J. Med. Genet., 2004 May;41:373-80; Weese-Mayer DE et al. Am. J. Respir. Crit. Care. Med. 2010 Mar;181(6):626-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Congenital central hypoventilation Pathogenic:1

May 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala241[25] variant in PHOX2B is a well-established pathogenic variant for CCHS, which has been reported in >100 affected individuals and was absent from ~ 4000 control chromosomes tested across multiple studies (Weese-Mayer 2010). This variant is a 15bp duplication within a polyalanine tract in exon 3 of the PHOX2 B gene, resulting in an expansion to a total of 25 alanine residues. It frequent ly occurs de novo, though autosomal dominant inheritance and somatic mosaicism h ave also been reported (Weese-Mayer 2010). While this variant typically causes c ongenital central hypoventilation, it has also been reported in individuals that presented with disease in infancy or childhood, raising the possibility of dela yed onset (Weese-Mayer 2010, Shimokaze 2015). In summary, this variant meets our criteria to be classified as pathogenic for CCHS in an autosomal dominant manne r. -

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: rs779557320; hg19: chr4-41748001;