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.2T>G (p.Met1Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229509

102647 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ba014c57-1ba6-4480-9f90-191b39ba497e

Approved on: 2019-07-07

Published on: 2019-07-07

HGVS expressions

NM_000277.2:c.2T>G

NM_000277.2(PAH):c.2T>G (p.Met1Arg)

NC_000012.12:g.102917129A>C

CM000674.2:g.102917129A>C

NC_000012.11:g.103310907A>C

CM000674.1:g.103310907A>C

NC_000012.10:g.101835037A>C

NG_008690.1:g.5474T>G

NG_008690.2:g.46282T>G

NM_000277.1:c.2T>G

NM_001354304.1:c.2T>G

NM_000277.3:c.2T>G

ENST00000307000.7:c.-146T>G

ENST00000546844.1:c.2T>G

ENST00000547319.1:n.313T>G

ENST00000549111.5:n.98T>G

ENST00000551337.5:c.2T>G

ENST00000551988.5:n.91T>G

ENST00000553106.5:c.2T>G

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

Pathogenic

PVS1 PP4_Moderate PM2 PM3

PP3 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.M1R 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. 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. The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the pathogenic variant p.R408W (PMID: 10679941; PM3); BH4 deficiency was excluded (PP4_Moderate). The variant is sufficiently rare in control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP4_moderate, PVS1.

PVS1

PP4_Moderate

The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the known pathogenic p.R408W allele (PMID: 10679941). In both, BH4 deficiency was said to be excluded.

The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the known pathogenic p.R408W allele (PMID: 10679941). In both, BH4 deficiency was said to be excluded. PubMed:10679941

PM2

The variant is sufficiently rare in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (highest observed population frequency 0.0001, in the gnomAD African subpopulation), which is under the PAH-specific frequency cutoff of 0.0002 (PM2).

PM3

The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the known pathogenic p.R408W allele (PMID: 10679941).

The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the known pathogenic p.R408W allele (PMID: 10679941). PubMed:10679941

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

Loss of function start loss variant

Curation History

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