The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

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

CA286499

102633 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
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

Met criteria codes 4
PM3 PM2 PP4_Moderate PP3
Not Met criteria codes 3
BA1 BS1 PS3

Evidence Links 0

Expert Panel

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.
Met criteria codes
PM3
Detected with R408W (VarID 577, P) and R413P (VarID 592, P) in 2 separate patients
PM2
Absent from absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP.
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.
Not Met criteria codes
BA1
Absent from absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP.
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
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