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]

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

CA229482

102626 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM3 PM2 PVS1 PP4

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.

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

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.

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

PM5

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

Approved on: 2019-07-07

Published on: 2019-07-07

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