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.331C>T (p.Arg111Ter)

CA251526

581 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: a0f4f502-3d14-496e-92b6-b2160d5d9013

HGVS expressions

NM_000277.2:c.331C>T
NM_000277.2(PAH):c.331C>T (p.Arg111Ter)
NC_000012.12:g.102894756G>A
CM000674.2:g.102894756G>A
NC_000012.11:g.103288534G>A
CM000674.1:g.103288534G>A
NC_000012.10:g.101812664G>A
NG_008690.1:g.27847C>T
NG_008690.2:g.68655C>T
NM_000277.1:c.331C>T
NM_001354304.1:c.331C>T
NM_000277.3:c.331C>T
ENST00000307000.7:c.316C>T
ENST00000546844.1:c.331C>T
ENST00000548928.1:n.253C>T
ENST00000549111.5:n.427C>T
ENST00000550978.6:n.315C>T
ENST00000551337.5:c.331C>T
ENST00000551988.5:n.420C>T
ENST00000553106.5:c.331C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 3
PP4_Moderate PM3_Very Strong PVS1
Not Met criteria codes 1
PM2

Expert Panel

Evidence Links 5

Evidence submitted by expert panel
PAH VCEP
PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3_very-strong: Detected in trans with 6 known pathogenic variants: p.R158Q; p.R241C; p.R243Q; p.E280K; p.Y356*; p.R413P (PMID:15503242, 26322415). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4_Moderate, PM3_very-strong).
Met criteria codes
PP4_Moderate
Seen in multiple Chinese PKU patients. BH4 deficiency excluded.

PM3_Very Strong
Detected with: p.R158Q (P, 11 submitters); p.R241C (P, 7 submitters); p.R243Q (P, 7 submitters); p.E280K (P, 9 submitters); p.Y356* (P, 5 submitters); p.R413P (P, 6 submitters)

PVS1
Nonsense variant
Not Met criteria codes
PM2
Absent from 1000G, ESP. ExAC MAF=0.00029.
Approved on: 2019-04-09
Published on: 2019-04-09
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