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Variant: NM_000277.1(PAH):c.941C>A (p.Pro314His)

CA229867

102907 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: a3e4cda3-a69f-4eef-8f15-27c0a7fe9068
Approved on: 2023-12-30
Published on: 2023-12-30

HGVS expressions

NM_000277.1:c.941C>A
NM_000277.1(PAH):c.941C>A (p.Pro314His)
NC_000012.12:g.102846923G>T
CM000674.2:g.102846923G>T
NC_000012.11:g.103240701G>T
CM000674.1:g.103240701G>T
NC_000012.10:g.101764831G>T
NG_008690.1:g.75680C>A
NG_008690.2:g.116488C>A
ENST00000553106.6:c.941C>A
ENST00000307000.7:c.926C>A
ENST00000549247.6:n.700C>A
ENST00000551114.2:n.603C>A
ENST00000553106.5:c.941C>A
ENST00000635477.1:c.74-2492C>A
ENST00000635528.1:n.456C>A
NM_000277.2:c.941C>A
NM_001354304.1:c.941C>A
NM_000277.3:c.941C>A
NM_001354304.2:c.941C>A
NM_000277.3(PAH):c.941C>A (p.Pro314His)
More

Pathogenic

Met criteria codes 4
PM2_Supporting PM3_Very Strong PP4_Moderate PP3
Not Met criteria codes 2
BS3 PM5

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The NM_000277.1(PAH):c.941C>A (p.Pro314His) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.91) (PP3). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3
Met criteria codes
PM2_Supporting
Absent from all pop databases.
PM3_Very Strong
It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914).
Retrospective study, large cohort of patients. Specific genotypes found in supplementary table 1. PubMed:23690520
PP4_Moderate
It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914).
PP3
All predictive software agree on damaging effect. REVEL=0.91
Not Met criteria codes
BS3
It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3).
PAH activity analysis. Site directed mutagenesis, transfected COS-1 cells. Enzyme activity measured as conversion of L-[14C]phe to L-[14C]tyr. Use both standard cDNA expression system and a new Intinic plasmid system which incorporates intronic sequences. Standard cDNA method demonstrates 15% and intinic system demonstrates 5% residual enzyme activity. PubMed:18590700
PM5
two other variants (c.940C>T and 940C>A) are both VUS in ClinVar, but provisionally pathogenic in recent curation efforts
Curation History
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