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_000277.3(PAH):c.463C>T (p.Arg155Cys)

CA6748917

554011 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 19342cb3-0d9a-4dcc-a710-deb9494e5f3d

HGVS expressions

NM_000277.3:c.463C>T

NM_000277.3(PAH):c.463C>T (p.Arg155Cys)

NM_000277.1:c.463C>T

NM_000277.2:c.463C>T

NM_001354304.1:c.463C>T

NM_001354304.2:c.463C>T

ENST00000307000.7:c.448C>T

ENST00000549111.5:n.559C>T

ENST00000551988.5:n.530+10820C>T

ENST00000553106.5:c.463C>T

NC_000012.12:g.102866642G>A

CM000674.2:g.102866642G>A

NC_000012.11:g.103260420G>A

CM000674.1:g.103260420G>A

NC_000012.10:g.101784550G>A

NG_008690.1:g.55961C>T

NG_008690.2:g.96769C>T

Likely Pathogenic

PP4_Moderate PP3 PM5 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID: 27121329). 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. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3.

PP4_Moderate

Identified in a patient with mild HPA. The current cutoff value for Phe is 120 µmol/L. Mild HPA is classified as Phe between 360–600 μmol/L. 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.

PubMed:27121329

PP3

SIFT, PolyPhen2, and MutationTaster support a deleterious effect on the gene or gene product. REVEL=0.952

PM5

Two other missense variants at this amino acid residue in ClinVar: p.Arg155Pro (expert panel) and p.Arg155His (expert panel). p.Arg115Pro is predicted to be likely pathogenic and p.Arg155His is predicted as pathogenic.

PM3

p.[Arg155Cys];[Gly289Arg]. Segregation analysis was done. PMID=27121329

PM2

Extremely low frequency in gnomAD (MAF=0.00007) and ExAC (MAF=0.00003). The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.

Approved on: 2020-10-15

Published on: 2020-10-15

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