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_000277.3(PAH):c.320A>G (p.His107Arg)

CA354151

225134 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 43c0e463-29fc-4579-ad14-55bf5d1fab63

HGVS expressions

NM_000277.3:c.320A>G

NM_000277.3(PAH):c.320A>G (p.His107Arg)

NM_000277.1:c.320A>G

NM_000277.2:c.320A>G

NM_001354304.1:c.320A>G

NM_001354304.2:c.320A>G

ENST00000307000.7:c.305A>G

ENST00000546844.1:c.320A>G

ENST00000548928.1:n.242A>G

ENST00000549111.5:n.416A>G

ENST00000550978.6:n.304A>G

ENST00000551337.5:c.320A>G

ENST00000551988.5:n.409A>G

ENST00000553106.5:c.320A>G

NC_000012.12:g.102894767T>C

CM000674.2:g.102894767T>C

NC_000012.11:g.103288545T>C

CM000674.1:g.103288545T>C

NC_000012.10:g.101812675T>C

NG_008690.1:g.27836A>G

NG_008690.2:g.68644A>G

Pathogenic

PP4 PM3_Very Strong PM2

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4.

PP4

This variant was documented 22 times in patients with PAH deficiency (>120 μmol/L Phe) Patients with BH4 cofactor deficiency were excluded by BH4 loading. PMID: 28982351

PM3_Very Strong

This variant was detected in trans with 16 pathogenic variants in patients with PKU; p.Arg111* (P) 1.0pts, p.Arg400Thr (P) 1.0pts, p.Val399= (P) 1.0pts, p.Val399= (P) 1.0pts, p.Arg241Cys (P) 1.0pts, p.Arg241Cys (P) 1.0pts, p.Arg413Pro (P) 1.0pts, p.Gly257Val (P) 1.0pts,, p.His107Arg 0.5 pts, p.Arg243Gln (P) 1.0pts, p.His220Pro (P) 1.0pts, p.Arg176* (P) 1.0pts,, p.Arg243Gln (P) 1.0pts, p.Arg243Gln (P) 1.0pts, p.Val230Ile (P) 1.0pts, p.Ile65Thr (P) 1.0pts PMID: 28982351

PM2

This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099).

PP3

Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2).

Approved on: 2020-12-09

Published on: 2021-01-15

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