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_000277.2(PAH):c.770G>A (p.Gly257Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229751

102829 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3f08bcbb-a332-40a0-8792-4b57e3608475

Approved on: 2025-04-18

Published on: 2025-04-18

HGVS expressions

NM_000277.2:c.770G>A

NM_000277.2(PAH):c.770G>A (p.Gly257Asp)

NC_000012.12:g.102852887C>T

CM000674.2:g.102852887C>T

NC_000012.11:g.103246665C>T

CM000674.1:g.103246665C>T

NC_000012.10:g.101770795C>T

NG_008690.1:g.69716G>A

NG_008690.2:g.110524G>A

ENST00000553106.6:c.770G>A

ENST00000307000.7:c.755G>A

ENST00000549247.6:n.529G>A

ENST00000553106.5:c.770G>A

NM_000277.1:c.770G>A

NM_001354304.1:c.770G>A

NM_000277.3:c.770G>A

NM_001354304.2:c.770G>A

Likely Pathogenic

PM3_Supporting PM2_Supporting PP3_Strong PP4 PM5

PM1

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 c.770G>A variant in PAH is a missense variant predicted to cause substitution of Glycine by Aspartic acid at amino acid 257 (p.Gly257Asp). At least one patient with this variant displayed plasma Phenylalanine > 1200 μmol/L, which is highly specific for PAH deficiency; BH4 deficiency was not reported to be ruled out (PP4, PMID: 10693064, 26666653). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a SCORE of 0.995, which is above the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_strong). Another missense variant c.770G>T, (p.Gly257Val) [ClinVar Variation ID102830] in the same codon has been classified as pathogenic for PAH deficiency by the ClinGen PAH VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4, PM2_supporting, PP3_strong, PM5. (PAH VCEP specifications version 2.0.0; 01/03/2025).

PM3_Supporting

Detected with L311P, Pathogenic by PAH VCEP, unknown phase. PMID: 26666653

Genotype c. [770G>A]; [932 T>C]/ p. [Gly257Asp]; [Leu311Pro] (VarID 578, Pathogenic/Likely Pathogenic) PubMed:26666653

PM2_Supporting

Absent from gnomAD v4.1

PP3_Strong

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.995

PP4

G257D seen on 2 HPA alleles in 2 patients. BH4 deficiency not ruled out. 1 patient with classic PKU (Phe > 1200 μmol/L) PMID: 10693064, PMID: 26666653

We tested for the genetic PAH locus in 151 patients with hyperphenylalaninaemia (containing 15 sib pairs), corresponding to 272 unrelated alleles. G257D was seen on 1 allele. PubMed:10693064

A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. G257D was observed in 1 patient with classic PKU. PubMed:26666653

PM5

p.Gly257Val is Pathogenic by PAH VCEP

PM1

Do not apply if PP3_strong applies

Curation History

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