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.199T>C (p.Ser67Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229481

102625 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 41884c41-0039-4205-b495-a83f4fcef082

Approved on: 2023-03-16

Published on: 2023-03-16

HGVS expressions

NM_000277.2:c.199T>C

NM_000277.2(PAH):c.199T>C (p.Ser67Pro)

NC_000012.12:g.102894888A>G

CM000674.2:g.102894888A>G

NC_000012.11:g.103288666A>G

CM000674.1:g.103288666A>G

NC_000012.10:g.101812796A>G

NG_008690.1:g.27715T>C

NG_008690.2:g.68523T>C

ENST00000553106.6:c.199T>C

ENST00000307000.7:c.184T>C

ENST00000546844.1:c.199T>C

ENST00000548677.2:n.286T>C

ENST00000548928.1:n.121T>C

ENST00000549111.5:n.295T>C

ENST00000550978.6:n.183T>C

ENST00000551337.5:c.199T>C

ENST00000551988.5:n.288T>C

ENST00000553106.5:c.199T>C

ENST00000635500.1:n.167T>C

NM_000277.1:c.199T>C

NM_001354304.1:c.199T>C

NM_000277.3:c.199T>C

NM_001354304.2:c.199T>C

NM_000277.3(PAH):c.199T>C (p.Ser67Pro)

Pathogenic

PM3_Very Strong PP4_Moderate PP3 PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3.

PM3_Very Strong

Detected in trans with: L48S (PMID: 8592329, parental testing performed), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) (PMID: 26351554, parental testing performed). p.R408W(c.1222C>T) (3 patients), p.R252W(c.754C>T) (2 patients) parental testing not reported PMID: 24350308

Patient III-4 genotype: L48S (maternal)/S67P (paternal). L48S: VarID608, Pathogenic. PubMed:8592329

A total of 218 alleles from109 individuals from 40 PKU families (40 PKU patients and their parents) were tested for S67P. Observed mutations in the patients were inherited from their parents. s67p/s67p; 2 patients, s67p/ivs10nt-11: 7 patients; s67p/r261q: 3 patients; r408q/s67p: 1 patient; s67p/r252w: 1 patient. PubMed:26351554

PP4_Moderate

S67P was detected in 1 PKU patient. DHPR deficiency was excluded. PMID: 8533759

A total of 121 Northern Irish families with HPA (111 with PKU and 10 with MHP) were investigated. Dihydrobiopterin reductase deficiency was excluded. S67P was detected on 1 allele. PubMed:8533759

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954)

PM2

Extremely low frequency in ExAC (MAF=0.00002)

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.