ClinVar Miner

Submissions for variant NM_003924.4(PHOX2B):c.227G>C (p.Ser76Thr)

gnomAD frequency: 0.00018  dbSNP: rs532711949
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565021 SCV000674217 benign Hereditary cancer-predisposing syndrome 2022-09-13 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000643944 SCV000765631 uncertain significance Haddad syndrome 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 76 of the PHOX2B protein (p.Ser76Thr). This variant is present in population databases (rs532711949, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PHOX2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 486030). 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 with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000764535 SCV000895621 uncertain significance Congenital central hypoventilation; Neuroblastoma, susceptibility to, 2 2018-10-31 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000565021 SCV002535392 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-04 criteria provided, single submitter curation
GeneDx RCV002510925 SCV002820359 uncertain significance not provided 2023-09-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics RCV003471903 SCV004203973 uncertain significance Neuroblastoma, susceptibility to, 2 2024-03-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003945354 SCV004757653 uncertain significance PHOX2B-related disorder 2023-12-11 no assertion criteria provided clinical testing The PHOX2B c.227G>C variant is predicted to result in the amino acid substitution p.Ser76Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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