Submissions for variant NM_003924.4(PHOX2B):c.691_698dup (p.Gly234fs)

dbSNP: rs2153112779

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385104	SCV001584849	pathogenic	Haddad syndrome	2022-04-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly234Alafs*78) in the PHOX2B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the PHOX2B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with features of congenital central hypoventilation syndrome (PMID: 15657873, 17637745, 26375764, 29696799, 30092902). In at least one individual the variant was observed to be de novo. This variant is also known as 689–696dup8. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002368223	SCV002661933	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-27	criteria provided, single submitter	clinical testing	The c.691_698dupGGCCCGGG pathogenic mutation, located in coding exon 3 of the PHOX2B gene, results from a duplication of GGCCCGGG at nucleotide position 691, causing a translational frameshift with a predicted alternate stop codon (p.G234Afs*78). This mutation has been described in multiple individuals with congenital central hypoventilation syndrome (CCHS), including a family in which three generations were variably affected with CCHS, central hypoventilation, Hirschsprung disease, and neuroblastoma (Trochet D et al. Am. J. Hum. Genet., 2005 Mar;76:421-6; Raabe EH et al. Oncogene, 2008 Jan;27:469-76; Low KJ et al. Pediatr. Pulmonol., 2014 Oct;49:E140-3; Byers HM et al. Am. J. Med. Genet. A, 2018 06;176:1398-1404). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV004590368	SCV005079265	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 81 amino acids are replaced with 77 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and at GeneDx (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29696799, 24799442, 15657873, 30092902, 29098737, 17637745, 25975378, 33958749, 34308366, 25070313)
PreventionGenetics, part of Exact Sciences	RCV004753303	SCV005356686	pathogenic	PHOX2B-related disorder	2024-04-22	no assertion criteria provided	clinical testing	The PHOX2B c.691_698dup8 variant is predicted to result in a frameshift and premature protein termination (p.Gly234Alafs*78). This variant has been reported in multiple individuals with congenital central hypoventilation syndrome (CCHS) (Trochet et al. 2005. PubMed ID: 15657873; Low et al 2014. PubMed ID: 24799442; Byers et al 2018. PubMed ID: 29696799). This variant has not been reported in a large population database, and is not reported in the ClinVar database. Frameshift variants in PHOX2B are expected to be pathogenic. This variant is interpreted as pathogenic.