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]

Variant: NM_000277.3(PAH):c.824C>T (p.Pro275Leu)

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CA229793

102855 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d6d14bd0-a2b2-4507-b74e-14bc74734d32

Approved on: 2022-07-30

Published on: 2022-07-30

HGVS expressions

NM_000277.3:c.824C>T

NM_000277.3(PAH):c.824C>T (p.Pro275Leu)

NC_000012.12:g.102852833G>A

CM000674.2:g.102852833G>A

NC_000012.11:g.103246611G>A

CM000674.1:g.103246611G>A

NC_000012.10:g.101770741G>A

NG_008690.1:g.69770C>T

NG_008690.2:g.110578C>T

ENST00000553106.6:c.824C>T

ENST00000307000.7:c.809C>T

ENST00000549247.6:n.583C>T

ENST00000553106.5:c.824C>T

NM_000277.1:c.824C>T

NM_000277.2:c.824C>T

NM_001354304.1:c.824C>T

NM_001354304.2:c.824C>T

Pathogenic

PP4_Moderate PM5 PM2 PM3_Very Strong PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.824 C>T (p.Pro275Leu) variant in PAH was reported in individuals affected with PAH deficiency in trans with various pathogenic variants: IVS4-1G>A (PMID 26600521); p.His170Gln (PMID 28982351,26600521); p.Arg241Cys (PMID 26600521); p.Lys42del (PMID 27243974); and p.Tyr414Cys (without phasing, PMID 12501224). This variant was absent in population databases. Two pathogenic variants are found in the same codon (p.Pro275Ser and p.Pro275Arg). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PM5, PP3, PP4_moderate.

PP4_Moderate

Variant was detected in a patient affected with PKU. A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. Variant was detected in a patient affected with PKU. PMID: 12501224

PM5

Two ClinVar variants found in the same codon (p.Pro275Ser) and (p.Pro275Arg) and classified as pathogenic by an expert panel.

PM2

This variant is absent from population databases gnomAD and ExAC

PM3_Very Strong

This variant was seen in trans with various ClinVar reported pathogenic variants: IVS4-1G>A (reviewed by an expert panel PMID 26600521); p.His170Gln (PMID 28982351,26600521); p.Arg241Cys (reviewed by an expert panel PMID 26600521); and p.Lys42del reported as likely pathogenic in ClinVar (PMID 27243974). Seen with a ClinVar reported pathogenic variant p.Tyr414Cys without phasing (PMID 12501224) . Points=4.5

PP3

Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). REVEL= 0.92

Curation History

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