ClinVar Miner

Submissions for variant NM_003924.4(PHOX2B):c.422G>A (p.Arg141Gln)

dbSNP: rs1733941453
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002327374 SCV002632794 pathogenic Hereditary cancer-predisposing syndrome 2016-10-18 criteria provided, single submitter clinical testing The p.R141Q pathogenic mutation (also known as c.422G>A), located in coding exon 2 of the PHOX2B gene, results from a G to A substitution at nucleotide position 422. The arginine at codon 141 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in unrelated pediatric patients affected by congenital central hypoventilation syndrome and Hischprung disease, with some subjects also diagnosed with neuroblastoma (Trochet D et al, Am J Hum Genet. 2005 Mar;76(3):421-6; Berry-Kravis et al, Am J Respir Crit Care Med 2006,174:1139-1144). Co-transfection assays revealed impaired interactions with transcriptional coactivator CREB-binding protein (Wu HT et al, Hum Mutat. 2009 Apr;30(4):655-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV003517297 SCV004293176 pathogenic Haddad syndrome 2023-07-14 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects PHOX2B function (PMID: 19058226, 27013732). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the PHOX2B protein (p.Arg141Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital central hypoventilation syndrome (PMID: 15657873, 16888290, 29543228, 34012823). ClinVar contains an entry for this variant (Variation ID: 869127). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PHOX2B protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV001078156 SCV001244207 pathogenic Congenital central hypoventilation 2021-08-25 no assertion criteria provided literature only

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