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.3G>A (p.Met1Ile)

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Curation History
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CA229532

622 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6cb217d7-b360-4a26-8c17-bce833da85f1

Approved on: 2019-07-07

Published on: 2019-07-07

HGVS expressions

NM_000277.2:c.3G>A

NM_000277.2(PAH):c.3G>A (p.Met1Ile)

NC_000012.12:g.102917128C>T

CM000674.2:g.102917128C>T

NC_000012.11:g.103310906C>T

CM000674.1:g.103310906C>T

NC_000012.10:g.101835036C>T

NG_008690.1:g.5475G>A

NG_008690.2:g.46283G>A

NM_000277.1:c.3G>A

NM_001354304.1:c.3G>A

NM_000277.3:c.3G>A

NM_001354304.2:c.3G>A

ENST00000307000.7:c.-145G>A

ENST00000546844.1:c.3G>A

ENST00000547319.1:n.314G>A

ENST00000549111.5:n.99G>A

ENST00000551337.5:c.3G>A

ENST00000551988.5:n.92G>A

ENST00000553106.5:c.3G>A

ENST00000635500.1:n.29-4230G>A

Pathogenic

PP4_Moderate PM3_Strong PM2 PVS1 PS2_Moderate PP1

PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.3G>A (p.Met1Ile) variant is a 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. This variant has been detected in multiple patients with PKU, BH4 deficiency excluded. PMID: 1301947, 23514811 (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variants IVS12+1G>A (PMID: 1301947) and p.F55L (27121329) (PM3_Strong). This variant has been detected de novo (PS2_moderate; PMID: 1301947), and in affected siblings (PP1; 23514811) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PVS1, PM2, PP4_Moderate, PS2_moderate, PP1.

PP4_Moderate

Detected multiple patients with PKU, BH4 deficiency excluded. PMID: 1301947, 23514811

We describe the detection of a de novo mutation in the phenylalanine hydroxylase gene in a Norwegian phenylketonuria (PKU) patient. This novel mutation, M1I, disrupts the start codon of the gene by a G to A transition. The compound heterozygote genotype (IVS-12/M1I) of this patient predicts that no phenylalanine hydroxylase enzyme is formed, thus leading to a severe classical PKU. A pretreatment serum phenylalanine value of 1,592 umol/liter and a phenylalanine tolerance at age 4 years of 20 mg/kg/day in the patient. PubMed:1301947

Detected on 3 alleles. Patients with transient HPA or with HPA due to a defect in the synthesis or recycling of the cofactor BH4 were excluded. PubMed:23514811

PM3_Strong

detected in trans with a pathogenic variants IVS12+1G>A (PMID: 1301947) and p.F55L (27121329)

Same patients as Bueno, et al. Patients’ and their families’ genomic DNA was obtained from whole-blood samples and/or dried blood spots. Segregation analysis was done to rule out the presence of large genomic rearrangements. PubMed:27121329

The compound heterozygote genotype (IVS-12/M1I). He had inherited the IVS-12 mutation from his mother, and the haplotype 7 (hpt7) chromosome from his father. PubMed:1301947

Genotype in 2 siblings: p.M1I/F55L. PubMed:23514811

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

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.

PS2_Moderate

De novo (maternity and paternity confirmed in a patient with classical PKU. Strength decreased per SVI recommendations.

He had inherited the IVS-12 mutation from his mother, and the haplotype 7 (hpt7) chromosome from his father. Since the paternal chromosome did not carry the M1I mutation, paternity testing was carried out. Fingerprint patterns were fully compatible with paternity. The M1I mutation was not found in his mother or in two healthy brothers. PubMed:1301947

PP1

Cosegregation with disease in affected siblings (1 mPKU, 1 BHPA) . PMID: 23514811

Cosegregation with disease in affected siblings (1 mPKU, 1 BHPA) PubMed:23514811

PM5

Loss of function start loss variant

Curation History

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