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_000277.1(PAH):c.929C>A (p.Ser310Tyr)

CA229854

102898 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 98fab9fa-47b3-47c6-9bd9-1d833f7e4ee4

Approved on: 2025-10-12

Published on: 2025-10-12

HGVS expressions

NM_000277.1:c.929C>A

NM_000277.1(PAH):c.929C>A (p.Ser310Tyr)

NC_000012.12:g.102846935G>T

CM000674.2:g.102846935G>T

NC_000012.11:g.103240713G>T

CM000674.1:g.103240713G>T

NC_000012.10:g.101764843G>T

NG_008690.1:g.75668C>A

NG_008690.2:g.116476C>A

ENST00000553106.6:c.929C>A

ENST00000307000.7:c.914C>A

ENST00000549247.6:n.688C>A

ENST00000551114.2:n.591C>A

ENST00000553106.5:c.929C>A

ENST00000635477.1:c.74-2504C>A

ENST00000635528.1:n.444C>A

NM_000277.2:c.929C>A

NM_001354304.1:c.929C>A

NM_000277.3:c.929C>A

NM_001354304.2:c.929C>A

Pathogenic

PM5 PM3 PP3_Strong PS3_Supporting PM2_Supporting PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.1(PAH):c.929C>A (p.Ser310Tyr) variant is a missense variant in exon 9/13 in PAH. The variant has been found to result in <1% of wild-type PAH enzyme activity in cDNA and Intinc systems (PMID: 18590700), and has been found to result in high molecular weight aggregates without residual enzyme activity (PMID: 18538294) (PS3_supporting). It has been previously reported in a patient with mild hyperphenylalanemia in trans with p.F55L (Pathogenic/Likely Pathogenic in ClinVar); BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 12501224) (PM3; PP4_Moderate). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.991) (PP3_strong). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3; PP4_Moderate; PP3_strong

PM5

p.Ser310Phe Pathogenic by PAH VCEP

PM3

It has been previously reported in a patient with mild hyperphenylalanemia in trans with p.F55L (Pathogenic/Likely Pathogenic in ClinVar); BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 12501224) (PM3; PP4_Moderate).

Patient #7 S310Y/F55L (pathogenic per clinVar) – with BH4 responsive mild hyperphe (>600umol/L @dx) S310Y is novel in this paper PubMed:12501224

PP3_Strong

All predictive software agree on damaging effect REVEL = 0.991

PS3_Supporting

Ho, 2008. Both standard cDNA and intinic systems suggest this variant has <1% enzyme activity. PMID: 18590700

PAH activity analysis. Site directed mutagenesis, transfected COS-1 cells. Enzyme activity measured as conversion of L-[14C]phe to L-[14C]tyr. Use both standard cDNA expression system and a new Intinic plasmid system which incorporates intronic sequences. Both systems predict <1% enzyme activity for this variant. PubMed:18590700

PM2_Supporting

Not found in any population databases

PP4_Moderate

BH4 defect excluded in all patients with urine pterins and DHPR activity. PubMed:12501224

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.