ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.684A>C (p.Glu228Asp)

dbSNP: rs2136649225
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001375898 SCV001572862 likely pathogenic Phenylketonuria 2024-09-06 reviewed by expert panel curation The c.684A>C (p.Glu228Asp) variant in PAH is a missense variant in exon 6/13 that is predicted damaging by REVEL (REVEL score 0.688) (PP3_Supporting). It has been previously reported in one individual with PAH deficiency (960μmol/L Phe) with BH4 cofactor deficiency excluded (PMID: 28982351) (PP4_Moderate), who harbored it in trans with the known pathogenic/likely pathogenic variant p.Arg243Gln (ClinVar ID 591) (1pt; PM3_Moderate). A different missense variant at the same site, p.Glu228Lys, is classified as a VUS in ClinVar by the PAH VCEP (ID 120284); thus PM5 is not met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Moderate, PP4_Moderate, PP3_Supporting.

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