Submissions for variant NM_003924.4(PHOX2B):c.552C>T (p.Ser184=)

gnomAD frequency: 0.01029  dbSNP: rs17885216

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214751	SCV000269642	benign	not specified	2016-01-29	criteria provided, single submitter	clinical testing	p.Ser184Ser in exon 3 of PHOX2B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1.2% (765/66160) of European chromosomes, including 1 homozygote by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs17885216).
Invitae	RCV001507205	SCV000288023	benign	Haddad syndrome	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000214751	SCV000309886	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000232548	SCV000449543	benign	Congenital central hypoventilation	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000291806	SCV000449544	benign	Neuroblastoma, susceptibility to, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000214751	SCV000521682	benign	not specified	2017-11-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590390	SCV000698219	benign	not provided	2016-05-17	criteria provided, single submitter	clinical testing	Variant summary: The PHOX2B c.552C>T (p.Ser184Ser) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create a novel ESE site of SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1028/120536 control chromosomes (4 homozygotes) at a frequency of 0.0085286, which is approximately 10234 times the estimated maximal expected allele frequency of a pathogenic PHOX2B variant (0.0000008), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590390	SCV001157021	benign	not provided	2023-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024232	SCV001186214	benign	Hereditary cancer-predisposing syndrome	2018-06-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000291806	SCV004016556	benign	Neuroblastoma, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590390	SCV004150033	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PHOX2B: BP4, BP7, BS1, BS2
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000590390	SCV001797910	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000214751	SCV001808450	benign	not specified		no assertion criteria provided	clinical testing