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.1A>T (p.Met1Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229482

102626 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a966e463-522a-42df-a6bc-5c03d571d48d

Approved on: 2019-07-07

Published on: 2019-07-07

HGVS expressions

NM_000277.2:c.1A>T

NM_000277.2(PAH):c.1A>T (p.Met1Leu)

NC_000012.12:g.102917130T>A

CM000674.2:g.102917130T>A

NC_000012.11:g.103310908T>A

CM000674.1:g.103310908T>A

NC_000012.10:g.101835038T>A

NG_008690.1:g.5473A>T

NG_008690.2:g.46281A>T

NM_000277.1:c.1A>T

NM_001354304.1:c.1A>T

NM_000277.3:c.1A>T

ENST00000307000.7:c.-147A>T

ENST00000546844.1:c.1A>T

ENST00000547319.1:n.312A>T

ENST00000549111.5:n.97A>T

ENST00000551337.5:c.1A>T

ENST00000551988.5:n.90A>T

ENST00000553106.5:c.1A>T

ENST00000635500.1:n.29-4232A>T

Pathogenic

PP4 PM2 PVS1 PM3

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106); There are no other PAH RefSeq 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 was reported in trans with the pathogenic variant p.Arg241His (PM3) in 1 Mexican proband with mild PKU (PMID: 24941924; PP4). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PVS1.

PP4

Reported in 2 Mexican probands, one with mild PKU and 1 with classic PKU (PMID: 24941924); BH4 loading test was performed, but exclusion of BH4 deficiency via enzymatic or genetic testing was not performed (PP4).

c.1A>T detected on 3 alleles. Forty-eight Mexican PKU/HPA unrelated patients and their families were included. The genotypes, c.[1A>T];[1A>T], c.[1A>T];[722G>A] were observed in a classic and in a mild PKU patients, respectively. PubMed:24941924

PM2

The variant is absent in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

PVS1

The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106). There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. 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. PVS1 can be used at full strength per Steven Harrison.

PM3

Detected in trans with pathogenic variant p.Arg241His (PMID: 24941924)

It was previously reported in trans with the known pathogenic p.Arg241His allele (PM3) in 1 Mexican proband with mild PKU (PMID: 24941924); BH4 loading test was performed, but exclusion of BH4 deficiency via enzymatic or genetic testing was not performed (PP4) PubMed:24941924

PM5

7 additional variants in the same codon, 6 are pathogenic in ClinVar, p.Met1Val is pathogenic per PAH VCEP.

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.