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

Variant: NM_000277.2(PAH):c.158G>A (p.Arg53His)

CA229447

102601 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 0b0aa28d-6844-4b34-a270-410f26ce9504

HGVS expressions

NM_000277.2:c.158G>A
NM_000277.2(PAH):c.158G>A (p.Arg53His)
NC_000012.12:g.102912801C>T
CM000674.2:g.102912801C>T
NC_000012.11:g.103306579C>T
CM000674.1:g.103306579C>T
NC_000012.10:g.101830709C>T
NG_008690.1:g.9802G>A
NG_008690.2:g.50610G>A
NM_000277.1:c.158G>A
NM_001354304.1:c.158G>A
NM_000277.3:c.158G>A
ENST00000307000.7:c.143G>A
ENST00000546844.1:c.158G>A
ENST00000548677.2:n.245G>A
ENST00000548928.1:n.80G>A
ENST00000549111.5:n.254G>A
ENST00000550978.6:n.142G>A
ENST00000551337.5:c.158G>A
ENST00000551988.5:n.247G>A
ENST00000553106.5:c.158G>A
ENST00000635500.1:n.126G>A

Uncertain Significance

Met criteria codes 3
BS1 PP4_Moderate PM3
Not Met criteria codes 1
PP3

Evidence Links 2

Evidence submitted by expert panel
Phenylketonuria VCEP
PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4_moderate: Detected in multiple patients with hyperphenylalaninemia, BH4 deficiency excluded (PMID:24401910, 26322415); PM3: Detected in trans with pathogenic variant p.R243Q. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4_moderate, PM3).
Met criteria codes
BS1
MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes)
PP4_Moderate
Detected in multiple patients with mild hyperphenylalaninemia (MHP, Phe levels<10 mg/dl), BH4 deficiency excluded.

PM3
Detected in trans with p.R243Q (P, 7 submitters) PMID: 26322415

Not Met criteria codes
PP3
Conflicting predictions of pathogenicity: Disease causing in MutationTaster, Benign in Polyphen-2 (HVAR). REVEL=0.789.
Approved on: 2019-04-08
Published on: 2019-04-08
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