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.516G>T (p.Gln172His)

CA6748897

664621 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1a22d5d2-0724-4358-8520-7a45806690cb

HGVS expressions

NM_000277.3:c.516G>T

NM_000277.3(PAH):c.516G>T (p.Gln172His)

NC_000012.12:g.102855326C>A

CM000674.2:g.102855326C>A

NC_000012.11:g.103249104C>A

CM000674.1:g.103249104C>A

NC_000012.10:g.101773234C>A

NG_008690.1:g.67277G>T

NG_008690.2:g.108085G>T

ENST00000307000.7:c.501G>T

ENST00000553106.5:c.516G>T

NM_000277.1:c.516G>T

NM_000277.2:c.516G>T

NM_001354304.1:c.516G>T

NM_001354304.2:c.516G>T

Likely Pathogenic

PM3_Strong PP4_Moderate

PP3 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.516G>T (p.Gln172His) variant in PAH has been reported in multiple affected individuals (1-MHP, 1-classic PKU). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 26322415. This variant has a highest MAF (East Asian) of 0.00055 in gnomAD, which is above the PAH VCEP AF cutoff (0.0002). This variant was detected in trans with known pathogenic variants: p.R243Q (PMID: 26322415), R408Q (PMID: 26600521) and p.Arg111* (PMID: 28982351; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong.

PM3_Strong

Detected in trans with p.R243Q (P by 8 submitters in ClinVar) PMID: 26322415. In trans with R408Q (P by 5 submitters in ClinVar) PMID: 26600521. In trans with p.Arg111* (P, 6 submitters) PMID: 28982351

PP4_Moderate

Detected in multiple patients (1-MHP, 1-classic PKU). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 26322415

PP3

Conflicting predictions of pathogenicity: SIFT and MutationTaster (D), PolyPhen2 HVAR (B). REVEL=0.79.

PM2

highest MAF (East Asian) = 0.00055 in gnomAD. Above PAH VCEP AF cutoff (0.0002).

Approved on: 2019-11-17

Published on: 2021-04-09

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