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_000277.1(PAH):c.1159T>C (p.Tyr387His)

CA229363

102539 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 29f8cc29-9bc1-4b4f-aeb2-832664291950

HGVS expressions

NM_000277.1:c.1159T>C

NM_000277.1(PAH):c.1159T>C (p.Tyr387His)

NC_000012.12:g.102843686A>G

CM000674.2:g.102843686A>G

NC_000012.11:g.103237464A>G

CM000674.1:g.103237464A>G

NC_000012.10:g.101761594A>G

NG_008690.1:g.78917T>C

NG_008690.2:g.119725T>C

ENST00000553106.6:c.1159T>C

ENST00000307000.7:c.1144T>C

ENST00000549247.6:n.918T>C

ENST00000551114.2:n.821T>C

ENST00000553106.5:c.1159T>C

ENST00000635477.1:n.263T>C

ENST00000635528.1:n.674T>C

NM_000277.2:c.1159T>C

NM_001354304.1:c.1159T>C

NM_000277.3:c.1159T>C

NM_001354304.2:c.1159T>C

NM_000277.3(PAH):c.1159T>C (p.Tyr387His)

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong PP3

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1159T>C (p.Tyr387His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 21890392). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.L48S, p.Y204X (PMID: 21147011); p.T323del (PMID: 9169088); c.754C>T, p.Arg252Trp (PMID: 21890392); p.Ala395Pro (PMID: 23357515); p.R261Q, c.782G>A (PMID: 23690520). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

Y387H seen in 3 hyperphenylalaninemic patients. BH4 deficiency excluded by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011, PMID: 21890392

PM3_Strong

Y387H detected with L48S and Y204X. Both pathogenic in ClinVar. Parental analysis not performed. PMID: 21147011; delT323, p 2 submitters parental analysis not reported PMID: 9169088; c.754C>T, p.Arg252Trp (maternal) P 7 submitters PMID: 21890392; p.[Tyr387His]; [Ala395Pro] parental analysis not reported P 2 submitters PMID: 23357515; p.R261Q c.782G>A P 11 submitters parental studies not reported PMID: 23690520 3.5 pts

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL 0.94

PM5

Only missense variant found at this codon in ClinVar

Approved on: 2020-08-17

Published on: 2021-11-21

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