Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002227997 | SCV000644025 | uncertain significance | Haddad syndrome | 2017-05-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 100 of the PHOX2B protein (p.Arg100Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. In summary, this variant impacts PHOX2B function and has been observed in affected individual. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies demonstrate that this missense change impedes the DNA binding and transactivation activity of PHOX2B and suppresses cellular differentiation, but nuclear localization and cell proliferation are not affected (PMID: 16249188, 19058226, 23873030, 17637745). This variant has been reported to segregate with Hirschsprung disease and neuroblastic tumors in a single family (PMID: 15949893, 15024693). It has also been observed in an individual affected with sporadic congenital central hypoventilation syndrome (PMID: 17637745). ClinVar contains an entry for this variant (Variation ID: 6011). This variant is not present in population databases (ExAC no frequency). |
| Ambry Genetics | RCV002433444 | SCV002746152 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-10-28 | criteria provided, single submitter | clinical testing | The p.R100L variant (also known as c.299G>T), located in coding exon 2 of the PHOX2B gene, results from a G to T substitution at nucleotide position 299. The arginine at codon 100 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in three individuals of one family with tumors of neural crest origin; the proband had a multifocal abdominal ganglioneuroma removed at age 10, a sibling had an abdominal neuroblastoma removed at age 6 and two recurrences, and their father had a ganglioneuroma of the adrenal medulla removed at age 44. Two paternal first cousins with Hirschsprung disease also had this alteration, as well as two unaffected paternal relatives (Trochet D et al. Am. J. Hum. Genet., 2004 Apr;74:761-4; Bourdeaut F et al. Cancer Lett., 2005 Oct;228:51-8). In vitro analysis of the protein with this alteration demonstrated complete loss of DNA binding (Trochet D et al. Hum. Mol. Genet., 2005 Dec;14:3697-708). This variant was previously reported in the SNPDatabase as rs104893855. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| OMIM | RCV000006382 | SCV000026564 | risk factor | Neuroblastoma, susceptibility to, 2 | 2004-04-01 | no assertion criteria provided | literature only |