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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.932T>C (p.Leu311Pro)

CA251524

578 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Link to MONDO

UUID: 706ff8ea-57af-4045-8096-4b998668f6e7

HGVS expressions

NM_000277.2:c.932T>C

NM_000277.2(PAH):c.932T>C (p.Leu311Pro)

NC_000012.12:g.102846932A>G

CM000674.2:g.102846932A>G

NC_000012.11:g.103240710A>G

CM000674.1:g.103240710A>G

NC_000012.10:g.101764840A>G

NG_008690.1:g.75671T>C

NG_008690.2:g.116479T>C

NM_000277.1:c.932T>C

NM_001354304.1:c.932T>C

NM_000277.3:c.932T>C

NM_001354304.2:c.932T>C

ENST00000307000.7:c.917T>C

ENST00000549247.6:n.691T>C

ENST00000551114.2:n.594T>C

ENST00000553106.5:c.932T>C

ENST00000635477.1:n.74-2501T>C

ENST00000635528.1:n.447T>C

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

PP3 PM2 PP4_Moderate PM3_Strong PS3_Supporting

PS1 PM5

Evidence Links 8

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3.

PP3

all software agree on damaging effect. REVEL=0.976

PM2

1.0e-5 in ExAC, not found in other databases

PP4_Moderate

BH4 defect excluded in all patients (PMID: 9634518, PMID: 23842451)

BH4 responsiveness predicted with 48hr loading test Subjects – 183 patients in 6 dutch university medical centers Nov 2009 – Dec 2010 Single patient, I65T/L311P. with classic PKU. I65T is pathogenic in clinvar. Patient had no BH4 responsiveness. PubMed:23842451

7 centers in France, Italy, Belgium, Germany, Denmark 686 patients BH4 defect excluded in all patients 3 patients with this variant. PubMed:9634518

PM3_Strong

L311P/I65T (pathogenic per ClinVar) p.Y386C (P/LP) PMID: 22841515 p.R261Q (P 9 submitters) PMID: 21871829 c.842+5G>A (P/LP) PMID: 19609714 p.Gly257Asp (LP) PMID: 26666653 parental analysis not reported in trans with c.842+1G>A (p 2 submitters) PMID: 27121329

PubMed:26666653

PubMed:22841515

PubMed:21871829

PubMed:27121329

PubMed:19609714

PS3_Supporting

Enzyme activity <1% in both standard cDNA and intinic system.

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 PubMed:18590700

PS1

no other variants in this codon

PM5

no other variants in this codon

Approved on: 2020-02-22

Published on: 2020-02-22

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