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.1114A>T (p.Thr372Ser)

CA229350

102528 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d7e037fb-45b7-488f-98bc-920b7c13f9eb

HGVS expressions

NM_000277.1:c.1114A>T

NM_000277.1(PAH):c.1114A>T (p.Thr372Ser)

NC_000012.12:g.102843731T>A

CM000674.2:g.102843731T>A

NC_000012.11:g.103237509T>A

CM000674.1:g.103237509T>A

NC_000012.10:g.101761639T>A

NG_008690.1:g.78872A>T

NG_008690.2:g.119680A>T

ENST00000553106.6:c.1114A>T

ENST00000307000.7:c.1099A>T

ENST00000549247.6:n.873A>T

ENST00000551114.2:n.776A>T

ENST00000553106.5:c.1114A>T

ENST00000635477.1:n.218A>T

ENST00000635528.1:n.629A>T

NM_000277.2:c.1114A>T

NM_001354304.1:c.1114A>T

NM_000277.3:c.1114A>T

NM_001354304.2:c.1114A>T

NM_000277.3(PAH):c.1114A>T (p.Thr372Ser)

Likely Pathogenic

PP4_Moderate PM2 PM3_Strong

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.1114A>T (p.Thr372Ser) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8807319, 21147011, 30050108). This variant has an extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with multiple pathogenic/likely pathogenic variants: p.R408W, c.1066-11G>A (PMID: 21147011); p.A300S (PMID: 8807319); p.P281L (2 patients, LP), delF39 (PMID: 10947211). 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.

PP4_Moderate

T372S was found in 1 Turkish patient with HPA (PMID: 8807319), and 3 PKU patients where BH4 deficiency had been ruled out by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011; 1 CHinese patient with MHP, dihydropteridine reductase activity, urinary biopterin and neopterin ratio were assessed PMID: 30050108 2.5 pts

Single-strand conformational analysis was used to screen for genetic defects in all thirteen exons of the phenylalanine hydroxylase gene (PAH) in phenylketonuria and hyperphenylalaninemia patients in the Netherlands. Exons that showed a bandshift were sequenced directly. T372S was identified in 1 Turkish patient with HPA. PubMed:8807319

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). T372S was found in 3 patients. PubMed:21147011

PM2

Absent from ExAC, 1000G, ESP. Extremely low frequency in gnomAD (MAF=0.00001)

PM3_Strong

Seen with 5 pathogenic variants: R408W, IVS10-11G>A (parental analysis not reported, PMID: 21147011); A300S (parental analysis not reported, PMID: 8807319); P281L (2 patients, LP), delF39 (P 5 submitters) parental analysis not reported PMID: 10947211 2.5 pts

Proband 33: A300S (VarID92751, Pathogenic)/T372S PubMed:8807319

Seen in 1 patient, homozygous. Seen in 2nd patient with R408W (VarID577, Pathogenic). Seen in 3rd patient with IVS10-11G>A (VarID607, Pathogenic). PubMed:21147011

PP3

Conflicting predictions of pathogenicity: deleterious in SIFT and MutationTaster, benign in Polyphen2, REVEL=0.908

PM5

This variant is the only variant found in this codon in ClinVar.

Approved on: 2020-08-14

Published on: 2021-11-21

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