ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.827T>C (p.Met276Thr)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003079148 SCV003461636 pathogenic Phenylketonuria 2023-06-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met276 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8068076, 16256386, 16290003, 25894915, 29176022, 30459323, 30612563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 31102715). 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 PAH protein function. ClinVar contains an entry for this variant (Variation ID: 2152159). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 31102715). This variant is present in population databases (rs62508722, gnomAD 0.004%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 276 of the PAH protein (p.Met276Thr).
Baylor Genetics RCV003079148 SCV004201963 likely pathogenic Phenylketonuria 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV004721109 SCV005327151 likely pathogenic not provided 2023-12-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31102715, 32668217, 29499199)

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