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>T (p.Gly257Val)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229753

102830 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 86128709-27f5-48f5-93a6-695080b882ef

Approved on: 2020-11-14

Published on: 2022-03-11

HGVS expressions

NM_000277.2:c.770G>T

NM_000277.2(PAH):c.770G>T (p.Gly257Val)

NC_000012.12:g.102852887C>A

CM000674.2:g.102852887C>A

NC_000012.11:g.103246665C>A

CM000674.1:g.103246665C>A

NC_000012.10:g.101770795C>A

NG_008690.1:g.69716G>T

NG_008690.2:g.110524G>T

ENST00000553106.6:c.770G>T

ENST00000307000.7:c.755G>T

ENST00000549247.6:n.529G>T

ENST00000553106.5:c.770G>T

NM_000277.1:c.770G>T

NM_001354304.1:c.770G>T

NM_000277.3:c.770G>T

NM_001354304.2:c.770G>T

NM_000277.3(PAH):c.770G>T (p.Gly257Val)

Pathogenic

PP3 PM2 PM3_Very Strong PP4_Moderate

PS3 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.770G>T (p.Gly257Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 26503515). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.R408Q, p.Ser70del (PMID: 26322415); p.R111X (PMID: 14722928); p.Arg261Gln (PMID: 17502162); c.1068C>A (p.Y356*, PMID: 25894915); p.Arg252Trp, p.Arg243Gln, p.His107Arg, p.Leu255Ser (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.991

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3_Very Strong

Detected with R408Q (P), p.Ser70del (P-3 submitters) All mutations identified in patients were confirmed by analyzing parental DNA PMID: 26322415; R111X (P-7 submitters) parental analysis not reported PMID: 14722928; p.Arg261Gln (P-11 submitters), parental analysis not reported PMID: 17502162; .1068C>A (p.Y356* P-7 submitters) parental analysis not reported PMID: 25894915; p.Arg252Trp (P), p.Arg243Gln (P), S70del, p.His107Arg (P/LP), p.Tyr356*, p.Leu255Ser (P/LP). variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 28982351 9.0 pts

Genotype: c.[206_208delCTT];[770G>T]/ p.[P69_S70delinsP];[G257V] Genotype 2: c.[1223G>A];[770G>T]/ p.[R408Q] (VarID 612, Pathogenic);[G257V] PubMed:26322415

PP4_Moderate

G257V identified in on at least 11 PKU alleles, plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. G257V was detected on 11 alleles. PubMed:26503515

Exon 7 of the PAH gene was analyzed in 45 children affected with classic PKU from northern China by using PCR-SSCP technique and DNA direct sequencing. G257V was identified. PubMed:9575658

PS3

In vitro enzyme activity of 1% of wt PMID: 24401910

PM5

3 other variants in this codon, no clinical assertion in ClinVar

Curation History

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