ClinVar Miner

Submissions for variant NM_003924.3(PHOX2B):c.299G>T (p.Arg100Leu) (rs104893855)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544450 SCV000644025 uncertain significance Congenital central hypoventilation 2017-06-14 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. This variant is not present in population databases (ExAC no frequency). 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). 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). 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.
OMIM RCV000006382 SCV000026564 risk factor Neuroblastoma 2 2004-04-01 no assertion criteria provided literature only

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