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_000277.3(PAH):c.1162G>C (p.Val388Leu)

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CA229366

102541 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 77049e4f-86fd-47f5-9095-13c4877981c6

Approved on: 2020-10-16

Published on: 2020-10-16

HGVS expressions

NM_000277.3:c.1162G>C

NM_000277.3(PAH):c.1162G>C (p.Val388Leu)

NC_000012.12:g.102843683C>G

CM000674.2:g.102843683C>G

NC_000012.11:g.103237461C>G

CM000674.1:g.103237461C>G

NC_000012.10:g.101761591C>G

NG_008690.1:g.78920G>C

NG_008690.2:g.119728G>C

NM_000277.1:c.1162G>C

NM_000277.2:c.1162G>C

NM_001354304.1:c.1162G>C

NM_001354304.2:c.1162G>C

ENST00000307000.7:c.1147G>C

ENST00000549247.6:n.921G>C

ENST00000551114.2:n.824G>C

ENST00000553106.5:c.1162G>C

ENST00000635477.1:n.266G>C

ENST00000635528.1:n.677G>C

Pathogenic

PM5 PM2 PM3_Strong PP4_Moderate

PP3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1162G>C (p.Val388Leu) variant in PAH was reported in 3 patients with PAH deficiency (PMID: 27121329, 31623983) detected with the likely pathogenic variant p.Pro281Leu and the pathogenic variant p.Arg252Trp. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is a novel missense change at an amino acid residue where a different missense change p.Val388Met determined to be pathogenic has been seen before. This variant is present in Dominican populations at a minor allele frequency of 0.00052 (PAGE study). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_moderate.

PM5

PM5_met: 2 other missense variants at this residue in ClinVar: p.Val388Met P by 5 submitters and PAH EP (expert panel); p.Val388Ala LP by PAH EP

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC. This variant is present in Dominican populations at a minor allele frequency of 0.00052 (3828 chromosomes)(PAGE study).

PM3_Strong

PM3_strong: This variant was detected in trans with a likely pathogenic variant in 1 patient with moderate PKU (PMID: 27121329). This variant was detected in trans with a pathogenic variant in 2 patients with mild hyperphenylalaninemia (MHP)(PMID: 31623983). 27121329 - This variant was detected in trans with the likely pathogenic PAH variant p.Pro281Leu in 1 patient with moderate PKU. Parental analysis was performed to confirm compound heterozygosity. 31623983 - This variant was detected in trans with the pathogenic PAH variant p.Arg252Trp in 2 patients with mild hyperphenylalaninemia (MHP). Parental analysis was not performed to confirm compound heterozygosity.

PubMed:31623983

PubMed:27121329

PubMed:9452061

PP4_Moderate

PP4_moderate: This variant was documented 1 time in a patient with PAH deficiency. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329) 27121329, Aldámiz-Echevarría: This variant was documented 1 time in a Spanish patient with moderate PKU (MPKU). Phenylalanine plasma concentrations >120 μM were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

PP3

PP3_not met: Predicted to be tolerated (SIFT), benign (PolyPhen2), disease causing (MutationTaster). REVEL=0.678

Curation History

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