ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1216A>G (p.Ile406Val)

gnomAD frequency: 0.00001  dbSNP: rs749613899
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000758135 SCV000886621 likely pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.1216A>G (p.Ile406Val) variant in PAH is reported in an individual with PKU. Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were collected. (PMID: 26503515) This variant has a low frequency in ExAC/gnomAD (MAF=0.00016) and is absent from 1000G. A deleterious effect is predicted by SIFT, Polyphen, and MutationTaster. Another missense variant at this amino acid is interpreted as likely pathogenic by our PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP4_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV000758135 SCV003441280 likely pathogenic Phenylketonuria 2023-01-24 criteria provided, single submitter clinical testing 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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 406 of the PAH protein (p.Ile406Val). This variant is present in population databases (rs749613899, gnomAD 0.02%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 26503515, 30747360, 35193651). ClinVar contains an entry for this variant (Variation ID: 619167). This variant disrupts the p.Ile406 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23357515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Baylor Genetics RCV000758135 SCV004201965 likely pathogenic Phenylketonuria 2024-01-23 criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000758135 SCV005418362 likely pathogenic Phenylketonuria criteria provided, single submitter clinical testing PM2_Supporting+PM5+PP3_Moderate+PM3+PP4_Moderate

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