Submissions for variant NM_003924.4(PHOX2B):c.741_755del (p.Ala256_Ala260del)

dbSNP: rs775006915

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177186	SCV000229021	likely benign	not specified	2014-12-17	criteria provided, single submitter	clinical testing
Invitae	RCV000231391	SCV000288028	benign	Haddad syndrome	2024-01-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000177186	SCV000309889	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV001579675	SCV000572002	likely benign	not provided	2020-01-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17637745, 14566559)
Ambry Genetics	RCV000574621	SCV000674213	likely benign	Hereditary cancer-predisposing syndrome	2019-01-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000177186	SCV000731335	benign	not specified	2016-12-14	criteria provided, single submitter	clinical testing	p.Ala256_Ala260del (also known as p.Ala241[15]) in exon 3 of PHOX2B: This varian t is common in the general population and therefore believed to be benign (Gener eviews: www.ncbi.nlm.nih.gov/books/NBK1427/#ondine.Molecular_Genetics). It was d etected in 2% (63/3266) of East Asian chromosomes, including 2 homozygotes, by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 75006915). This variant represents a deletion of 5 alanine amino acids within a repeat sequence in this gene, for a total of 15 total repeats (The predominant n ormal allele contains 20 repeats).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001579675	SCV002009995	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000177186	SCV002064874	likely benign	not specified	2021-08-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574621	SCV002535408	benign	Hereditary cancer-predisposing syndrome	2020-10-26	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177186	SCV003929342	benign	not specified	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: PHOX2B c.741_755del15 (p.Ala256_Ala260del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. This variant is located to a poly-alanine repeat region, where the major allele contains a 20 alanine stretch, and this variant removes 5 alanines. The variant allele was found at a frequency of 0.0033 in 145318 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4000-fold of the estimated maximal expected allele frequency for a pathogenic variant in PHOX2B causing Neuroblastoma, Susceptibility Type, 2 phenotype (8.3e-07), strongly suggesting that the variant is benign. The variant, c.741_755del15 or equivalent protein level changes, have been reported in the literature in individuals affected with Neuroblastoma (e.g. Raabe_2008), however without providing evidence for causality. Similar 5 alanine deletion variants have also been reported in patients affected with Hirschsprung disease, with some of them noting mild neonatal respiratory disorders (Di Zanni_2017). Authors of this study also reported experimental evidence evaluating the impact of contractions of the polyalanine tract, and demonstrated that the -5Ala variant resulted in ~95% transactivation response compared to the WT on RET promoter, while greater contractions (-7Ala and -13Ala) resulted in significantly lower transactivation values (Di Zanni_2017), therefore authors of this study proposed that contractions of the 20 alanine stretch of the PHOX2B gene could increase the susceptibility to Hirschsprung disease (with mild neonatal respiratory disorders). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001579675	SCV004150029	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PHOX2B: BS1
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579675	SCV001808110	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579675	SCV001971336	likely benign	not provided		no assertion criteria provided	clinical testing