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.169-13T>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229460

102611 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 15d75bd7-63ed-440d-87a4-842eff5257aa

Approved on: 2020-08-17

Published on: 2021-12-12

HGVS expressions

NM_000277.2:c.169-13T>G

NM_000277.2(PAH):c.169-13T>G

NC_000012.12:g.102894931A>C

CM000674.2:g.102894931A>C

NC_000012.11:g.103288709A>C

CM000674.1:g.103288709A>C

NC_000012.10:g.101812839A>C

NG_008690.1:g.27672T>G

NG_008690.2:g.68480T>G

ENST00000553106.6:c.169-13T>G

ENST00000307000.7:c.154-13T>G

ENST00000546844.1:c.169-13T>G

ENST00000548677.2:n.256-13T>G

ENST00000548928.1:n.91-13T>G

ENST00000549111.5:n.265-13T>G

ENST00000550978.6:n.153-13T>G

ENST00000551337.5:c.169-13T>G

ENST00000551988.5:n.258-13T>G

ENST00000553106.5:c.169-13T>G

ENST00000635500.1:n.137-13T>G

NM_000277.1:c.169-13T>G

NM_001354304.1:c.169-13T>G

NM_000277.3:c.169-13T>G

NM_001354304.2:c.169-13T>G

NM_000277.3(PAH):c.169-13T>G

Likely Pathogenic

PP3 PP4_Moderate PM2 PM3_Strong

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.169-13T>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 9521426, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with pathogenic variants: IVS10-11G>A (PMID: 21147011); p.L213P (PMID: 9521426); p.R158Q (PMID: 12640344); p.Y356X (c.1068C > G in 1 patient and c.1068C > A in 1 patient, PMID: 30389586). Computational evidence support a deleterious effect on splicing. 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, PP3.

PP3

Potential alteration of splicing. MaxEnt: +1718. Broken WT Acceptor site. Splice AI: Splice-Altering (0.91); TraP Score: 0.435 (>99%ile, probably damaging)

PP4_Moderate

IVS2-13T>G was first reported in a Tuscan patient with Classic PKU. BH4 deficiency was ruled out by dosing the urinary pterins. PMID: 9521426 Also reported in a Turkish PKU patient with assessment of the PAH, PTS, and QDPR genes PMID: 21147011

This report identifies eight new mutations of the phenylalanine hydroxylase gene detected in Italian patients with hyperphenylalaninemia. 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 identificationof mutations in the PAH gene. Patient F84: IVS2nt-13 (splicing defect, classic PKU; Tuscany). PubMed:9521426

PM2

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

PM3_Strong

Detected with IVS10-11G>A (Pathogenic in ClinVar) parental analysis not reported (PMID: 21147011) and L213P (P/LP) PMID: 9521426; R158Q P 10 submitters), parental analysis not confirmed PMID: 12640344; p.Y356X (c.1068C > G in 1 patient, P 4 submitters; and c.1068C > A in 1 patient, P 7 submitters) parental analysis not reported PMID: 30389586 3.0 pts

IVS2-13T>G seen with IVS10-11G>A (VarID 607, Pathogenic). PubMed:21147011

IVS2nt-13 in F84 was maternally inherited. The second mutation was L213P (varID 92747, Pathogenic/LP). PubMed:9521426

PS3

6.7% enzyme activity in BioPKU, but literature reference not identified

Curation History

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