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.818C>T (p.Ser273Phe)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229785

598 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 75b9eddc-e554-4f4c-91a7-976ac6c27ba2

Approved on: 2018-08-10

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.818C>T

NM_000277.2(PAH):c.818C>T (p.Ser273Phe)

NC_000012.12:g.102852839G>A

CM000674.2:g.102852839G>A

NC_000012.11:g.103246617G>A

CM000674.1:g.103246617G>A

NC_000012.10:g.101770747G>A

NG_008690.1:g.69764C>T

NG_008690.2:g.110572C>T

NM_000277.1:c.818C>T

NM_001354304.1:c.818C>T

NM_000277.3:c.818C>T

ENST00000307000.7:c.803C>T

ENST00000549247.6:n.577C>T

ENST00000553106.5:c.818C>T

Likely Pathogenic

PP3 PM2 PM3_Strong PP4_Moderate

PM5

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC and gnomAD (1 allele); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978; PP4_Moderate: S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup. (PMID:1671881; PMID:8533759; PMID:9012412; PMID:24368688); PM3_Strong: Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines (PMID:24368688). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong).

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978

PM2

Extremely low frequency in ExAC and gnomAD (1 allele)

PM3_Strong

Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines

Patient 32 genotype: I65T/ S273F. Patient 111 genotype: S273F/ R408W. PubMed:24368688

PP4_Moderate

S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup.

The five patients reported here were born either in Belgium (four patients) or in north eastern France (one patient). All five children were diagnosed through systematic newborn screening programmes and met the criteria for typical PKU (low tolerance for dietary phenylalanine, averaging 250 mg/day). The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively). PubMed:1671881

One hundred and eleven patients, including seven families with two or more affected individuals, were recruited from the records of the NSW Newborn Screening Programme or from the PKU Clinic at the Children’s Hospital at Westmead, Sydney Australia. p.S273F was detected in 2 patients. PubMed:24368688

PKU patients from four centers in three countries of Great Britain were studied. S273F was detected on 2 Western Scotland alleles. PubMed:9012412

A total of 121 Northern Irish families with HPA (111 with PKU and 10 with MHP) were investigated, including virtually all patients born after 1972. dihydrobiopterin reductase deficiency was excluded. S273F was seen on 3 alleles. PubMed:8533759

PM5

S273F is the only variant in this codon in ClinVar

Curation History

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