Submissions for variant NM_003924.4(PHOX2B):c.741_758dup (p.Ala255_Ala260dup)

dbSNP: rs771383153

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267981	SCV001446531	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001267981	SCV001786215	pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	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)
AiLife Diagnostics, AiLife Diagnostics	RCV001267981	SCV002501973	pathogenic	not provided	2020-07-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379970	SCV002671260	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-17	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003333146	SCV004041407	pathogenic	Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	2023-06-17	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV003333146	SCV004232715	likely pathogenic	Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	2023-07-05	criteria provided, single submitter	research