ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.386A>G (p.Asp129Gly) (rs199475623)

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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 RCV000672629 SCV001146722 likely pathogenic Phenylketonuria 2019-04-05 reviewed by expert panel curation The c.386A>G (p.Asp129Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8981952). This variant has extremely low frequency in gnomAD (MAF: 0.00001; PM2). This variant was detected in trans with known pathogenic variant c.1066-11G>A (PM3; PMID: 27121329). Computational evidence supports a deleterious effect (PP3). 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.
Counsyl RCV000672629 SCV000797753 likely pathogenic Phenylketonuria 2018-02-08 criteria provided, single submitter clinical testing
Invitae RCV000672629 SCV001218441 pathogenic Phenylketonuria 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 129 of the PAH protein (p.Asp129Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed be homozygous in an individual affected with phenylketonuria (PMID: 9359039). ClinVar contains an entry for this variant (Variation ID: 102661). This variant has been reported to affect PAH protein function (PMID: 23559577). This variant disrupts the p.Asp129 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 26542770, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088908 SCV000119506 not provided not provided no assertion provided not provided

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