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_000277.1(PAH):c.1223G>A (p.Arg408Gln)

Curation Version - 1.0
Curation History
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CA229404

612 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f5c357c3-eebd-4738-b8e9-b9c74e4aa9f4

Approved on: 2018-08-05

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.1223G>A

NM_000277.1(PAH):c.1223G>A (p.Arg408Gln)

NC_000012.12:g.102840492C>T

CM000674.2:g.102840492C>T

NC_000012.11:g.103234270C>T

CM000674.1:g.103234270C>T

NC_000012.10:g.101758400C>T

NG_008690.1:g.82111G>A

NG_008690.2:g.122919G>A

NM_000277.2:c.1223G>A

NM_001354304.1:c.1223G>A

NM_000277.3:c.1223G>A

ENST00000307000.7:c.1208G>A

ENST00000551114.2:n.885G>A

ENST00000553106.5:c.1223G>A

ENST00000635477.1:n.327G>A

ENST00000635528.1:n.738G>A

Pathogenic

PP4_Moderate PS3 PP3 PM3_Strong

PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_Strong, PP3, PS3, PP4_Moderate).

PP4_Moderate

~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown

823 umol/L, BH4 status unknown PubMed:1312992

~830 uml/L w/o BH4 deficiency PubMed:9860305

PS3

Mutant enzyme activity of 46% in BioPKU

Residual enzyme activity of 55% PubMed:9860305

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3_Strong

In trans with R408W, IVS4-1G>A, R241C (ClinGen, P)

Patient 5: IVS4-1G>A (VarID102671, P/LP)+ R408Q. Patient 6: E6nt-96A>G (VarID590? P/LP)+ R408Q. Patients 17 + 18: R241C (VarID102803, P)+ R408Q. PubMed:14722928

In trans with R408W--(ClinGen, P). One patient homozygous for the mutation was found. PubMed:1312992

PM2

1000G MAF=0.00144

Curation History

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