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.*19G>T

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA6748669

255733 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fb349172-324d-471b-a9a9-6f13ed39de6c

Approved on: 2019-09-27

Published on: 2019-09-29

HGVS expressions

NM_000277.2:c.*19G>T

NM_000277.2(PAH):c.*19G>T

NC_000012.12:g.102839156C>A

CM000674.2:g.102839156C>A

NC_000012.11:g.103232934C>A

CM000674.1:g.103232934C>A

NC_000012.10:g.101757064C>A

NG_008690.1:g.83447G>T

NG_008690.2:g.124255G>T

NM_000277.1:c.*19G>T

NM_001354304.1:c.*19G>T

NM_000277.3:c.*19G>T

ENST00000307000.7:c.*19G>T

ENST00000551114.2:n.1040G>T

ENST00000553106.5:c.*19G>T

ENST00000635528.1:n.893G>T

Uncertain Significance

BS1 PP4

BP7 PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1.

BS1

Allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes

PP4

Found in 2 patients with PKU (1 Brazilian and 1 Italian). PMID: 12765842, PMID: 26210745

This alteration was found in one patient (Fig. 1B) and his mother, and was detected by sequence analysis and restriction endonuclease digestion. Presumably this alteration is associated with the disease for the following reasons: the patient inherited the R408Q mutation from his father which was in cis with the V245V polymorphism (Table 4), whereas the only other possible disease-causing lesion detected was 1378g → t, which was inherited from the patient’s mother based on Xmn1 restriction enzyme analysis, and was not present in 100 normal chromosomes. The other novel alteration IVS12nt-15t → c, was considered a polymorphism because it was found in three patients, two of whom had two previously described PAH disease-causing mutations (Table 4). PubMed:12765842

Detected on 1 allele, in cis with p.R408Q. PubMed:26210745

BP7

TraP score: 0.085 (benign)

PP3

TraP score: 0.085 (benign); HSF:Activation of an exonic cryptic donor site. (New site +62.32) Alteration of an exonic ESE site. Potential alteration of splicing. MaxENT 3' Motif:+1145.71.

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.