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.529G>C (p.Val177Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229610

102727 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: db42ee8e-361d-4756-8504-caeaf67f6741

Approved on: 2019-09-22

Published on: 2021-04-09

HGVS expressions

NM_000277.3:c.529G>C

NM_000277.3(PAH):c.529G>C (p.Val177Leu)

NC_000012.12:g.102855313C>G

CM000674.2:g.102855313C>G

NC_000012.11:g.103249091C>G

CM000674.1:g.103249091C>G

NC_000012.10:g.101773221C>G

NG_008690.1:g.67290G>C

NG_008690.2:g.108098G>C

ENST00000307000.7:c.514G>C

ENST00000553106.5:c.529G>C

NM_000277.1:c.529G>C

NM_000277.2:c.529G>C

NM_001354304.1:c.529G>C

NM_001354304.2:c.529G>C

Pathogenic

PM3_Very Strong PP4_Moderate PM2

PP3

Evidence Links 9

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.529G>C (p.Val177Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate). This variant has an extremely low allele frequency (Pop Max MAF=0.00005 ENF) in gnomAD (PM2). This variant was detected with pathogenic variants: F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID: 8659548, PMID: 16879198, PMID: 19609714, PMID: 23430918, PMID: 22391997, PMID: 22513348, PMID: 26666653 (PM3_very-strong. Computational prediction tools and conservation analysis do not agree. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong, PM2.

PM3_Very Strong

Detected with pathogenic variants F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID: 8659548, PMID: 16879198, PMID: 19609714, PMID: 23430918, PMID: 22391997, PMID: 22513348, PMID: 26666653

L48S+V177L. parental testing not reported. PubMed:16879198

[V177L]+[F39del]. parental testing not reported. PubMed:19609714

Allele 2: F39L Parental testing not reported. PubMed:8659548

Patient 5, Allele 2: p.R261Q. Patient 8, Allele 2: p.F55fs. parental testing not reported. PubMed:22391997

p.V177L: p.R408W. parental testing not reported. PubMed:23430918

Patient 50: p.R158Q/p.V177L. parental testing not reported. PubMed:22513348

c. [529G>C]; [561G>A] p.[Val177Leu];[Trp187*]. parental testing not reported. PubMed:26666653

PP4_Moderate

Detected in multiple patients with PAH deficiency. BH4 deficiency excluded in one report. PMID: 22526846

Detected on 1 allele from a hyperphenylalaninemic female. Patient A/3098/RCR-10, Phe level 400 (MHP) PubMed:8659548

p.V177L (c.529G>C) was detected in this cohort. Elevated phenylalanine concentrations were detected by newborn screening and confirmed by quantitative analysis of plasma amino acids. Analysis of urinary pterins and dihydropterine reductase assays were performed to exclude BH4 deficiency (Nenad Blau, Zurich, Switzerland). PubMed:22526846

183 patients from six Dutch university medical centres. Detected in the cohort. PubMed:23842451

PM2

Pop Max MAF=0.00005 ENF in gnomAD

PP3

Conflicting predictions: SIFT-D; PolyPhen2-B; MutationTaster-D

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.