ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.558_559del (p.Trp187fs)

gnomAD frequency: 0.00002  dbSNP: rs62517207
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000412455 SCV001448658 pathogenic Phenylketonuria 2020-10-30 reviewed by expert panel curation The c.558_559del (p.Trp187fs) variant in PAH has been reported in 1 Indian PKU patient; Phe = 1240umol/L; BH4 deficiency not excluded (PMID: 24130151; PP4). The variant was detected in the homozygous state, both parents confirmed to be heterozygous (consanguineous) - 0.5 points (PMID: 24130151; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 6 out of 13 coding exons; 6 out of total exons) (PVS1). This variant was reported in gnomad with MAF = 0.00016 in South Asian population (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting.
Counsyl RCV000412455 SCV000485336 likely pathogenic Phenylketonuria 2015-11-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000412455 SCV001590437 pathogenic Phenylketonuria 2022-10-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102734). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 24130151). This variant is present in population databases (rs62517207, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Trp187Glyfs*12) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518).
Baylor Genetics RCV000412455 SCV004209618 pathogenic Phenylketonuria 2023-08-15 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088983 SCV000119587 not provided not provided no assertion provided not provided

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