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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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

CA229447

102601 (ClinVar)

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

HGVS expressions

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

Uncertain Significance

Met criteria codes 3
PP4_Moderate BS1 PM3
Unmet criteria codes 1
PP3

Expert Panel

Evidence Links 2

Evidence submitted by expert panel
PAH 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
PP4_Moderate
Detected in multiple patients with mild hyperphenylalaninemia (MHP, Phe levels<10 mg/dl), BH4 deficiency excluded.

BS1
MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes)
PM3
Detected in trans with p.R243Q (P, 7 submitters) PMID: 26322415

Unmet 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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