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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

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

CA273113

92738 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance

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

Met criteria codes 4
PM3_Very Strong PP3 PM2 PP4_Moderate

Expert Panel

Evidence Links 2

Evidence submitted by expert panel
PAH 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.
Met criteria codes
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.

PP3
Predicted deleterious in SIFT, PolyPhen2, Mutation Taster, REVEL=0.897
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).
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

Approved on: 2020-07-24
Published on: 2020-07-24
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