ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.613G>A (p.Glu205Lys)

dbSNP: rs63083560
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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 RCV001071178 SCV001370880 likely pathogenic Phenylketonuria 2020-06-01 reviewed by expert panel curation The c.613G>A (p.Glu205Lys) variant in PAH has been reported in 2 individuals with mild-moderate and classic PKU, in trans with pathogenic variant p.Arg243* in both patients (PMID: 27121329). This variant is absent in population databases. 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_strong, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001071178 SCV001236466 likely pathogenic Phenylketonuria 2019-12-08 criteria provided, single submitter clinical testing This variant disrupts the p.Glu205 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 11139255, 22841515), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 27121329). ClinVar contains an entry for this variant (Variation ID: 102759). 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"). 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. This sequence change replaces glutamic acid with lysine at codon 205 of the PAH protein (p.Glu205Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089009 SCV000119613 not provided not provided no assertion provided not provided

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