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.212G>A (p.Arg71His)

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CA286499

102633 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 41f440f5-e9e9-4eb2-b622-59574cfefc61

Approved on: 2019-09-29

Published on: 2019-09-29

HGVS expressions

NM_000277.1:c.212G>A

NM_000277.1(PAH):c.212G>A (p.Arg71His)

NC_000012.12:g.102894875C>T

CM000674.2:g.102894875C>T

NC_000012.11:g.103288653C>T

CM000674.1:g.103288653C>T

NC_000012.10:g.101812783C>T

NG_008690.1:g.27728G>A

NG_008690.2:g.68536G>A

NM_000277.2:c.212G>A

NM_001354304.1:c.212G>A

NM_000277.3:c.212G>A

ENST00000307000.7:c.197G>A

ENST00000546844.1:c.212G>A

ENST00000548677.2:n.299G>A

ENST00000548928.1:n.134G>A

ENST00000549111.5:n.308G>A

ENST00000550978.6:n.196G>A

ENST00000551337.5:c.212G>A

ENST00000551988.5:n.301G>A

ENST00000553106.5:c.212G>A

ENST00000635500.1:n.180G>A

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3

BS1 PS3 BA1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.212G>A (p.Arg71His) variant in PAH has been reported in multiple individual with PAH deficiency with BH4 deficiency excluded (PP4_Moderate; PMID: 10495930, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variant p.R408W (PM3). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP4_Moderate

Found in 1 patient with mild hyperphenylalaninemia (PMID: 10495930), 2 alleles in Chinese PKU cohort (BH4 deficiency assessed) PMID: 26503515

PP3

In-silico predictions largely predict it to be damaging (SIFT-D, Polyphen2-P, MutationTaster-D, REVEL=0.749.

PM2

Absent from absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP.

PM3

Detected with R408W (VarID 577, P) and R413P (VarID 592, P) in 2 separate patients

BS1

Absent from absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP.

PS3

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

BA1

Absent from absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP.

Curation History

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