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]

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Variant: NM_000277.2(PAH):c.733G>A (p.Val245Met)

CA229722

102809 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dd013c62-06e0-42a1-b503-4a26dfce4cf1

Approved on: 2020-11-10

Published on: 2022-02-20

HGVS expressions

NM_000277.2:c.733G>A

NM_000277.2(PAH):c.733G>A (p.Val245Met)

NC_000012.12:g.102852924C>T

CM000674.2:g.102852924C>T

NC_000012.11:g.103246702C>T

CM000674.1:g.103246702C>T

NC_000012.10:g.101770832C>T

NG_008690.1:g.69679G>A

NG_008690.2:g.110487G>A

ENST00000553106.6:c.733G>A

ENST00000307000.7:c.718G>A

ENST00000549247.6:n.492G>A

ENST00000553106.5:c.733G>A

NM_000277.1:c.733G>A

NM_001354304.1:c.733G>A

NM_000277.3:c.733G>A

NM_001354304.2:c.733G>A

NM_000277.3(PAH):c.733G>A (p.Val245Met)

Pathogenic

PM5 PM2 PM3_Strong PP4 PP3

PS3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID: 26542770) and c.913-7A>G (PMID: 29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). 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_strong, PM2, PM5, PP4, PP3.

PM5

V245L (varID 102810, Pathogenic 3 submitters), V245A Pathogenic- 10 submitters, V245E Pathogenic - 1 submitter/Invitae,

PM2

Absent from ExAC, gnomAD, 1000G, ESP.

PM3_Strong

V245M detected in trans with E178G (pathogenic) Parental testing confirmed PMID: 26542770; c.913-7A>G (P/LP by multiple submitters) variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 29316886

V245M detected in trans with c.532G>A, p.E178G (VarID 92746, Pathogenic). Parental testing confirmed that the two mutations identified in the 368 patients all were present in trans. PubMed:26542770

PP4

V245M seen in 1 patient with MHP. BH4 deficiency not ruled out.

We included 376 PKU patients from 362 unrelated Danish families, representing all PKU patients in Denmark from 1967–2014 referred to the National Center for PKU. All patients had PKU according to biochemical criteria. C.733G>A seen in Patient 7 with MHP (210 umol/l serum Phe). PubMed:26542770

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.942.

PS3

p.Val245Met did not affect mRNA transcription in the eukaryotic expression system (HEK293T cells), however, mutant PAH proteins were markedly decreased in both prokaryotic (E. coli) and eukaryotic expression system. Protein activity not assessed, only expression. PMID: 29653233

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