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.464G>A (p.Arg155His)

CA229559

102686 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0857614c-284a-4342-821b-887439f4d6aa

HGVS expressions

NM_000277.2:c.464G>A

NM_000277.2(PAH):c.464G>A (p.Arg155His)

NC_000012.12:g.102866641C>T

CM000674.2:g.102866641C>T

NC_000012.11:g.103260419C>T

CM000674.1:g.103260419C>T

NC_000012.10:g.101784549C>T

NG_008690.1:g.55962G>A

NG_008690.2:g.96770G>A

NM_000277.1:c.464G>A

NM_001354304.1:c.464G>A

NM_000277.3:c.464G>A

ENST00000307000.7:c.449G>A

ENST00000549111.5:n.560G>A

ENST00000551988.5:n.530+10821G>A

ENST00000553106.5:c.464G>A

Pathogenic

PP4_Moderate PP3 PP1 PM2 PM3_Strong

PS3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID: 9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID: 18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1.

PP4_Moderate

R155H was detected in 1 patient with hyperphenylalaninemia, defect in tetrahydrobiopterin metabolism was excluded PMID: 9634518

In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. R155H was detected in 1 patient. PubMed:9634518

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.948)

PP1

Patients 15-18 (siblings) had genotype p.D143G/p.R155H

Patients 15-18 (siblings) had genotype p.D143G/p.R155H PubMed:18937047

PM2

low frequency in ExAC/gnomad (MAF=0.00012) in EA population

PM3_Strong

Detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745).

Patient genotype: IVS4+5G>T c.441+5G>T (P/LP, 8 submitters)/p.R155H c.464G>A PubMed:26210745

Patient 17 genotype: R111X (P, 7 submitters) + R155H. When sequence alteration was identified, paternal or maternal origin was determined whenever the parental DNA was available. PubMed:24401910

Patients 15-18 (siblings) had genotype p.D143G/p.R155H PubMed:18937047

2 patients: R243Q (P, 8 submitters) /R155H and V399V (not in ClinVar)/R155H PubMed:23932990

PS3

R155H mutant retained approximately one‐half specific activity (p.R155H, 55%).

The mutations p.D143G, p.R155H, p.L348V, p.R408W and p.P416Q were introduced in the human PAH cDNA on the pMALc2 expression vector by polymerase chain reaction‐based site‐directed mutagenesis. Tetrameric full‐length wild‐type PAH (wt‐PAH) and mutant PAH human enzymes were expressed in E. coli as fusion proteins with maltose‐binding protein (MBP). PAH enzyme activity was measured at 25°C for 1 min. R155H mutant retained approximately one‐half specific activity (p.R155H, 55%). PubMed:18937047

Approved on: 2019-04-07

Published on: 2019-04-07

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