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_000277.2(PAH):c.809G>A (p.Arg270Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229781

102846 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: de83f450-c3c7-4554-9f5f-553c705d3691

Approved on: 2020-06-08

Published on: 2020-06-08

HGVS expressions

NM_000277.2:c.809G>A

NM_000277.2(PAH):c.809G>A (p.Arg270Lys)

NC_000012.12:g.102852848C>T

CM000674.2:g.102852848C>T

NC_000012.11:g.103246626C>T

CM000674.1:g.103246626C>T

NC_000012.10:g.101770756C>T

NG_008690.1:g.69755G>A

NG_008690.2:g.110563G>A

NM_000277.1:c.809G>A

NM_001354304.1:c.809G>A

NM_000277.3:c.809G>A

NM_001354304.2:c.809G>A

ENST00000307000.7:c.794G>A

ENST00000549247.6:n.568G>A

ENST00000553106.5:c.809G>A

Pathogenic

PS3_Supporting PM3_Very Strong PP3 PM2 PP4_Moderate

PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID: 27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID: 21871829); and IVS4+5G>T (PMID: 23856132). Computational prediction tools and conservation analysis support a deleterious effect. 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, PP3, PS3_supporting.

PS3_Supporting

11% residual PAH activity. PMID: 27620137

11% residual PAH activity reported in in vitro expression studies. PubMed:27620137

PM3_Very Strong

detected with IVS10nt-11G>A (2 patients P 7 submitters), L348V (P 8 submitters), S349P (P 5 submitters), R158Q (pathogenic), E390G (P 8 submitters), D415N (P 8 submitters). parental analysis not reported PMID: 21871829; with IVS4+5G>T (P 7 submitters) parental analysis not reported PMID: 23856132 4.0 pts

Seen in multiple patients with classic PKU (>1200uM). In homozgotes state and in trans with IVS10nt-11G>A, L348K, S349P, R158Q, E390G, D415N. Predicted residual enzyme activity >1. PubMed:21871829

Seen in multiple individuals with classic PKU. In homozygous state and in trans with IVS4+5G>T, pretreatment PKU >1200 umol/L PubMed:23856132

PP3

SIFT, Polyphen and Mutation Taster predict deleterious effect.

PM2

absent from 1000G. Seen in low frequencies in ExAC and gnomAD (MAF=0.00016)

PP4_Moderate

Seen in multiple individuals in multiple studies with classic PKU. BH4 deficiency excluded. PMID: 21871829, PMID: 23856132

Seen in multiple patients with classic PKU (>1200uM). In homozgotes state and in trans with IVS10nt-11G>A, L348K, S349P, R158Q, E390G, D415N. Predicted residual enzyme activity >1. BH4 excluded. PubMed:21871829

Seen in multiple individuals with classic PKU. In homozygous state and in trans with IVS4+5G>T, pretreatment PKU >1200 umol/L PubMed:23856132

PM5

R270G and R270S have no interpretations in ClinVar

Curation History

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