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.716G>A (p.Gly239Asp)

CA229707

102798 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: da3f74a6-7bfc-4899-8d98-a2722a49cff5

Approved on: 2025-08-15

Published on: 2025-08-15

HGVS expressions

NM_000277.1:c.716G>A

NM_000277.1(PAH):c.716G>A (p.Gly239Asp)

NC_000012.12:g.102852941C>T

CM000674.2:g.102852941C>T

NC_000012.11:g.103246719C>T

CM000674.1:g.103246719C>T

NC_000012.10:g.101770849C>T

NG_008690.1:g.69662G>A

NG_008690.2:g.110470G>A

ENST00000553106.6:c.716G>A

ENST00000307000.7:c.701G>A

ENST00000549247.6:n.475G>A

ENST00000553106.5:c.716G>A

NM_000277.2:c.716G>A

NM_001354304.1:c.716G>A

NM_000277.3:c.716G>A

NM_001354304.2:c.716G>A

Pathogenic

PP3_Strong PM3_Strong PM2_Supporting PP4_Moderate

PM5

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_000277.3(PAH):c.716G>A variant is PAH is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 239 (p.Gly239Asp). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) and showed defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4_moderate; PMID 26503515;PMID: 16256386; PMID 12905706; PMID:23932990). This variant has been detected in at least 4 individuals. Of those individuals, 3 were compound heterozygous for the variant and distinct pathogenic (2)/likely pathogenic (1) variant (V399V, R241C, p.R241Pfs*100) and 3 of those were confirmed in trans by parental analysis and sanger sequencing (PM3_strong, PMID: 16256386; PMID: 30050108). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.982, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3_strong, PP4_Moderate, PP3_strong. Version 2.0, 7/16/2024.

PP3_Strong

The computational predictor REVEL gives a score of 0.982, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong).

PM3_Strong

This variant has been detected in at least 4 individuals. Of those individuals, 3 were compound heterozygous for the variant and distinct pathogenic (2)/likely pathogenic (1) variant (V399V, R241C, p.R241Pfs*100) and 3 of those were confirmed in trans by parental analysis and sanger sequencing (PM3_strong, PMID: 16256386; PMID: 30050108).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PP4_Moderate

At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) and showed defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4_moderate; PMID 26503515;PMID: 16256386; PMID 12905706; PMID:23932990).

Ten novel mutations were first time identified in Chinese PKU population as I65T, S70del, G239D, R241fsdelG, L255S, P281L, G346R, L367fsinsC, R400S and Ivsllnt2t-->c. PubMed:12905706

Reported in Table 1 The spectrum of PAH mutations in Chinese Mainland PKU patients. PubMed:26503515

PM5

G239V uncertain significance. S/A no interpretation

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.