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]

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Variant: NM_000277.1(PAH):c.508C>G (p.His170Asp)

CA273111

92744 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8845817f-fc6b-4d7f-93b6-a072aeee8cba

Approved on: 2018-07-28

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.508C>G

NM_000277.1(PAH):c.508C>G (p.His170Asp)

NC_000012.12:g.102866597G>C

CM000674.2:g.102866597G>C

NC_000012.11:g.103260375G>C

CM000674.1:g.103260375G>C

NC_000012.10:g.101784505G>C

NG_008690.1:g.56006C>G

NG_008690.2:g.96814C>G

NM_000277.2:c.508C>G

NM_001354304.1:c.508C>G

NM_000277.3:c.508C>G

ENST00000307000.7:c.493C>G

ENST00000549111.5:n.604C>G

ENST00000551988.5:n.530+10865C>G

ENST00000553106.5:c.508C>G

Pathogenic

PM3_Strong PS3 PP3 PP4 PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID: 11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID: 17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID: 11385716; PMID: 24941924). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM3_Strong

PM3_Strong

Detected in trans with R261X, c.60+5G>T, c.1315+1G>A (known pathogenic variants) PMID: 11385716; PMID: 24941924

H170D was present in 2 Hispanics whose genotypes were H170D/H170D and H170D/R261X. PubMed:11385716

c.508C>G/c.60+5G>T (VarID:102751, Pathogenic); c.508C>G/c.1315+1G>A (VarID:576, Pathogenic); c.508C>G/c.842+1G>A (VarID599, P/LP) PubMed:24941924

PS3

43% residual enzyme activity PMID: 17935162

43% residual enzyme activity PubMed:17935162

PP3

Predicted deleterious in SIFT, Polyphen2, MutationsTaster. REVEL=0.938

PP4

H170D present in 1 patient with HPA, and 1 patient with benign persistent HPA. PMID: 11385716

H170D was present in 2 Hispanics with PKU. one with hyperphenylalaninemia (R261X/H170D genotype), the other with benign persistent hyperphenylalaninemia (homozygous H170D). PubMed:11385716

PM2

Absent in ExAC, 1000G, ESP. Extremely low frequency in gnomAD (0.00018)

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