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

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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

PP4 BS1

PP3 BP7

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.

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

BS1

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

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.

BP7

TraP score: 0.085 (benign)

Curation History

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