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_000277.1(PAH):c.601C>T (p.His201Tyr)

CA229643

102752 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 31fc727e-9400-49e3-9c17-63e7b2fb8748

Approved on: 2019-11-10

Published on: 2020-01-25

HGVS expressions

NM_000277.1:c.601C>T

NM_000277.1(PAH):c.601C>T (p.His201Tyr)

NC_000012.12:g.102855241G>A

CM000674.2:g.102855241G>A

NC_000012.11:g.103249019G>A

CM000674.1:g.103249019G>A

NC_000012.10:g.101773149G>A

NG_008690.1:g.67362C>T

NG_008690.2:g.108170C>T

NM_000277.2:c.601C>T

NM_001354304.1:c.601C>T

NM_000277.3:c.601C>T

ENST00000307000.7:c.586C>T

ENST00000549111.5:n.697C>T

ENST00000553106.5:c.601C>T

Likely Pathogenic

PM3_Strong PP4_Moderate PM2

PP3 PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.

PM3_Strong

In trans with IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137), Both Pathogenic in ClinVar

Patient F99: Genotype H201Y/IVS10nt546 (VarID:607, Pathogenic); Phenotype non-PKU HPA. PubMed:9521426

Patient 44 Genotype H201Y/R158Q (VarID 587, Pathogenic in ClinVar) PubMed:16198137

PP4_Moderate

Seen in 2 patient with HPA and BH4 defects were ruled out (PMID: 16198137)

Patient F99: Genotype H201Y/IVS10nt546; Phenotype non-PKU HPA. The occurrence of defects involving homeostasis or synthesis of the phenylalanine hydroxylase cofactor (BH4) was ruled out by dosing the urinary pterins as well as by identification of mutations in the PAH gene. PubMed:9521426

All patients born in Lombardy (Italy) between January 2000 and December 2004, and affected by HPA (107 patients) were classiffed after BH4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH4-responsiveness. Patient 44 Genotype H201Y/R158Q; Phenotype MHP (plasma phe 120–360 umol/L). PubMed:16198137

PM2

3.964e-6 in gnomAD; Low frequency in control population database

PP3

Conflicting predictions: Tolerated in SIFT, Damaging in MutationTaster

PM5

p.His201Arg (VarID 102753) Clinical significance not provided in ClinVar

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