ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.665A>T (p.Asp222Val)

dbSNP: rs62507319
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001789760 SCV002032206 likely pathogenic Phenylketonuria 2020-08-17 reviewed by expert panel curation The c.665A>T (p.Asp222Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 9012412). This variant is absent in population databases. This variant was detected with pathogenic variants p.R243X and p.R241H (PMID: 21147011). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001789760 SCV003441221 pathogenic Phenylketonuria 2023-09-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp222 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9429153, 10598814). 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: 102776). This missense change has been observed in individuals with phenylketonuria (PMID: 21147011, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 222 of the PAH protein (p.Asp222Val).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089027 SCV000119632 not provided not provided no assertion provided not provided

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