Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000277.3(PAH):c.593_614del (p.Tyr198fs)

CA229639

102747 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5677a6d7-20db-4d63-b6fa-b69008c476be

HGVS expressions

NM_000277.3:c.593_614del

NM_000277.3(PAH):c.593_614del (p.Tyr198fs)

NM_000277.1:c.593_614del

NM_000277.2:c.593_614del

NM_001354304.1:c.593_614del

NM_001354304.2:c.593_614del

ENST00000307000.7:c.578_599del

ENST00000549111.5:n.689_710del

ENST00000553106.5:c.593_614del

NC_000012.12:g.102855228_102855249del

CM000674.2:g.102855228_102855249del

NC_000012.11:g.103249006_103249027del

CM000674.1:g.103249006_103249027del

NC_000012.10:g.101773136_101773157del

NG_008690.1:g.67354_67375del

NG_008690.2:g.108162_108183del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM2 PP4_Moderate PVS1 PM3_Very Strong

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.593_614del (p.Tyr198fs) frameshift variant in PAH is predicted to undergo nonsense mediated-decay. This variant was reported in 9 patients with PAH deficiency (PMID 27121329, 26210745, 21871829, 26666653). A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329, 21871829). This variant was detected in trans with 3 pathogenic/LP variants (PMID 27121329) and in 6 patients with pathogenic/LP variants with unknown phasing (PMID 26210745, 21871829, 26666653). This variant is absent in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 very strong, PM2, and PP4 moderate.

PM2

Absent from gnomAD.

PP4_Moderate

Reported in 3 patients with PAH deficiency. (mild HPA-NT (2) <360 μmol /1 And CPKU (1) >1200 μmol /1) A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). In an Italian cohort, 3 patients with classic PKU were observed (PMID 26210745) and 2 with unspecified PAH deficiency in a Portuguese cohort (PMID 21871829). Diagnosis was confirmed after exclusion of BH4 deficiency by evaluating urinary pterin levels and erythrocyte dihydropteridine reductase activity (PMID 21871829). In a French cohort one patient was identified with classic PKU (cPKU, Phe > 1200 μmol/L) (PMID 26666653).

PVS1

Frameshift variant 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)

PM3_Very Strong

Detected in trans with pathogenic/LP variants p.Val230Ile (n=2) and p.Ser349Pro (n=1). Segregation analysis was done (PMID 27121329). 6 pathogenic/LP variants with unknown phasing were heterozygous with this variant: c.1241A>G, c.781T>C, c.1315+2T>C, p.R158Q, p.R243X, c.969+1G>A (PMID 26210745, 21871829, 26666653).

PubMed:27121329

Approved on: 2020-07-24

Published on: 2020-07-24

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