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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.1(PAH):c.631C>A (p.Pro211Thr)

CA229666

102766 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f456bf29-4223-48fc-b2ed-ac0b0bc873a3

HGVS expressions

NM_000277.1:c.631C>A

NM_000277.1(PAH):c.631C>A (p.Pro211Thr)

NC_000012.12:g.102855211G>T

CM000674.2:g.102855211G>T

NC_000012.11:g.103248989G>T

CM000674.1:g.103248989G>T

NC_000012.10:g.101773119G>T

NG_008690.1:g.67392C>A

NG_008690.2:g.108200C>A

ENST00000553106.6:c.631C>A

ENST00000307000.7:c.616C>A

ENST00000549111.5:n.727C>A

ENST00000553106.5:c.631C>A

NM_000277.2:c.631C>A

NM_001354304.1:c.631C>A

NM_000277.3:c.631C>A

NM_001354304.2:c.631C>A

Pathogenic

PP4_Moderate PM3_Very Strong PP3 PM2

PM5 PS3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.631C>A (p.Pro211Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 11708866, 21147011, 1619813). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: IVS10-11G>A (4 patients, PMID: 21147011); p.R261Q in 2 unrelated patients (PMID: 11708866); p.R408W (PMID: 9429153); p.G272X (PMID: 16198137). Computational prediction tools and conservation analysis support a deleterious effect on the protein. 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.

PP4_Moderate

P211T seen in 8 patients with PKU. BH4 deficiency excluded in 6 patients. (PMID: 11708866, PMID: 21147011; PMID: 1619813)

Discordant metabolic phenotypes (mild PKU and MHP) were observed in two unrelated patients bearing the same R261Q/P211T genotype. PubMed:11708866

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). p.P211T was seen with IVS10-11G>A in 4 patients. PubMed:21147011

PM3_Very Strong

P211T found with IVS10-11G>A in 4 patients, parental analysis not reported PMID: 21147011; and R261Q in 2 unrelated patients, parental analysis not reported. PMID: 11708866, both Pathogenic; R408W (P), parental analysis not reported PMID: 9429153; G272X (P) parental analysis not reported PMID: 16198137. 4.0 pts

R261Q/P211T (VarID582, Pathogenic/Likely Pathogenic) PubMed:11708866

p.P211T was seen with IVS10-11G>A (VarID 607, Pathogenic) in 4 patients. PubMed:21147011

PP3

Damaging in SIFT, Polyphen, Mutation Taster

PM2

Not found in ExAC, 1000G, ESP. MAF=0.00004 in gnomAD

PM5

p.Pro211Leu (VarID 120283) Likely Pathogenic in ClinVar 3 submitters

PS3

Analyzed in vitro by the pCDNA3/COS-7 eukaryotic expression system and found an activity of 72% compared to normal PAH.

Analyzed three missense mutations L41F, T92I, and P211T in vitro by the pCDNA3/COS-7 eukaryotic expression system and found an activity of 10, 76, and 72%, respectively, compared to normal PAH. PubMed:11708866

Approved on: 2020-07-02

Published on: 2021-07-09

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