ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.443G>A (p.Gly148Asp)

dbSNP: rs1555205655
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001093513 SCV001250545 likely pathogenic Phenylketonuria 2020-01-26 reviewed by expert panel curation The c.443G>A (p.Gly148Asp) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 21147011, 15589814). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant IVS4nt5G>T (c.441+5G>T). Computational evidence supports 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_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001093513 SCV002275948 likely pathogenic Phenylketonuria 2021-05-26 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has been observed in individual(s) with phenylketonuria (PMID: 15589814, 21147011). ClinVar contains an entry for this variant (Variation ID: 872837). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 148 of the PAH protein (p.Gly148Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant disrupts the p.Gly148 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8535445, 7726156, 9012412, 10679941, Invitae). 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.

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