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.2T>C (p.Met1Thr)

CA312807

203873 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 44685f9b-a06f-4d15-a65b-2a3632a64ab6

Approved on: 2019-07-07

Published on: 2019-07-07

HGVS expressions

NM_000277.1:c.2T>C

NM_000277.1(PAH):c.2T>C (p.Met1Thr)

NC_000012.12:g.102917129A>G

CM000674.2:g.102917129A>G

NC_000012.11:g.103310907A>G

CM000674.1:g.103310907A>G

NC_000012.10:g.101835037A>G

NG_008690.1:g.5474T>C

NG_008690.2:g.46282T>C

NM_000277.2:c.2T>C

NM_001354304.1:c.2T>C

NM_000277.3:c.2T>C

ENST00000307000.7:c.-146T>C

ENST00000546844.1:c.2T>C

ENST00000547319.1:n.313T>C

ENST00000549111.5:n.98T>C

ENST00000551337.5:c.2T>C

ENST00000551988.5:n.91T>C

ENST00000553106.5:c.2T>C

ENST00000635500.1:n.29-4231T>C

Likely Pathogenic

PM2 PVS1

PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

c.2T>C (p.Met1Thr) is a null PAH variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has an extremely low frequency in ExAC, ESP, gnomAD. However, it has not been reported in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2.

PM2

extremely low frequency in ExAC, ESP, gnomAD (MAF=0.00012)

PVS1

Null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. Kept at full strength per Steven Harrison.

PP4

This variant has not been reported in a patient with PAH deficiency to our knowledge

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.