ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.828G>A (p.Met276Ile)

gnomAD frequency: 0.00001  dbSNP: rs62514954
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666601 SCV000790917 uncertain significance Phenylketonuria 2017-04-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000666601 SCV003216204 likely pathogenic Phenylketonuria 2022-06-22 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 551519). This missense change has been observed in individual(s) with a positive newborn screening result for PAH-related disease (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 276 of the PAH protein (p.Met276Ile).

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