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.204A>T (p.Arg68Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA273113

92738 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6b7ec948-f2f5-4aeb-8fae-b588b8369c3d

Approved on: 2020-07-24

Published on: 2020-07-24

HGVS expressions

NM_000277.3:c.204A>T

NM_000277.3(PAH):c.204A>T (p.Arg68Ser)

NC_000012.12:g.102894883T>A

CM000674.2:g.102894883T>A

NC_000012.11:g.103288661T>A

CM000674.1:g.103288661T>A

NC_000012.10:g.101812791T>A

NG_008690.1:g.27720A>T

NG_008690.2:g.68528A>T

NM_000277.1:c.204A>T

NM_000277.2:c.204A>T

NM_001354304.1:c.204A>T

NM_001354304.2:c.204A>T

ENST00000307000.7:c.189A>T

ENST00000546844.1:c.204A>T

ENST00000548677.2:n.291A>T

ENST00000548928.1:n.126A>T

ENST00000549111.5:n.300A>T

ENST00000550978.6:n.188A>T

ENST00000551337.5:c.204A>T

ENST00000551988.5:n.293A>T

ENST00000553106.5:c.204A>T

ENST00000635500.1:n.172A>T

Pathogenic

PP4_Moderate PM2 PP3 PM3_Very Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). It was detected in trans with several pathogenic variants including p.Ala300Ser, p.Asp415Asn, p.Arg158Gln, and c.1315+1G>A (PMID 27121329, 22841515). This variant was found in low frequency in gnomAD (MAF=0.00016) and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3 very strong, PM2, PP4 Moderate, and PP3.

PP4_Moderate

Reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity PMID 27121329

PubMed:23764561

PM2

extremely low frequency in gnomAD (MAF=0.00016). Present in European (non-Finnish) populations at a frequency of 0.00007 and all populations at a 0.00004 frequency of (ExAC).

PP3

Predicted deleterious in SIFT, PolyPhen2, Mutation Taster, REVEL=0.897

PM3_Very Strong

Detected in trans with several pathogenic variants including p.Ala300Ser, Asp415Asn , Arg158Gln, and c.1315+1G>A. Additionally, found homozygous (p.[Arg68Ser];[Arg68Ser] (n=2) )with mild HPA. Segregation analysis was done in PMID 27121329. Segregation analysis was also in PMID 22841515.

PubMed:26666653

Curation History

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