ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1252A>C (p.Thr418Pro)

dbSNP: rs62644501
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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 RCV000672448 SCV001762300 pathogenic Phenylketonuria 2020-06-08 reviewed by expert panel curation The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176*, EX6-96A＞G, p.Tyr356*, p.Arg111* (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.
Counsyl RCV000672448 SCV000797554 pathogenic Phenylketonuria 2018-02-06 criteria provided, single submitter clinical testing
Invitae RCV000672448 SCV003441151 pathogenic Phenylketonuria 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 418 of the PAH protein (p.Thr418Pro). This variant is present in population databases (rs62644501, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 1301187, 26322415, 29499199, 29731766, 30747360, 31355225). ClinVar contains an entry for this variant (Variation ID: 102580). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088818 SCV000119409 not provided not provided no assertion provided not provided

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