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]

Link to SEPIO compliant JSON-LD document

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

CA229404

612 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f5c357c3-eebd-4738-b8e9-b9c74e4aa9f4

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 PM3_Strong PS3 PP3

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

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

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

PM2

1000G MAF=0.00144

Approved on: 2018-08-05

Published on: 2019-04-05

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.