The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000277.3(PAH):c.283A>T (p.Ile95Phe)

CA229507

102645 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: c61fa227-893e-4be0-9e02-2d7c1494af20
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.283A>T
NM_000277.3(PAH):c.283A>T (p.Ile95Phe)
NC_000012.12:g.102894804T>A
CM000674.2:g.102894804T>A
NC_000012.11:g.103288582T>A
CM000674.1:g.103288582T>A
NC_000012.10:g.101812712T>A
NG_008690.1:g.27799A>T
NG_008690.2:g.68607A>T
ENST00000553106.6:c.283A>T
ENST00000307000.7:c.268A>T
ENST00000546844.1:c.283A>T
ENST00000548677.2:n.370A>T
ENST00000548928.1:n.205A>T
ENST00000549111.5:n.379A>T
ENST00000550978.6:c.267A>T
ENST00000551337.5:c.283A>T
ENST00000551988.5:n.372A>T
ENST00000553106.5:c.283A>T
NM_000277.1:c.283A>T
NM_000277.2:c.283A>T
NM_001354304.1:c.283A>T
NM_001354304.2:c.283A>T
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Likely Pathogenic

Met criteria codes 3
PP4 PP3 PM3_Strong
Not Met criteria codes 3
PM1 PM5 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID: 10495930); p.R158Q, p.A403V, p.T323del (PMID: 18299955); and p.E280K (PMID: 31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4.
Met criteria codes
PP4
Reported in multiple patients with mild and moderate PKU, BH4 deficiency not ruled out PMID: 10495930
PP3
REVEL=0.658
PM3_Strong
I95F/R408W, Mendelian inheritance was confirmed. PMID: 10495930; R158Q (P), A403V(P), T323del (P), parental analysis not reported, PMID: 18299955; p.E280K (P by 11 submitters), parental analysis not reported PMID: 31623983; 3.0 pts
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
I95T is US by PAH VCEP
PM2
MAF is 0.0004908 (AJ) in gnomAD v4, which is too high for PM2 (<0.0002) and too low for BS1 (>0.002). Reported in an occasional patient INGD (Israeli National Genetic Database) and found in gnomAD uniquely among Ashkenazi Jews (100%) and in a significantly increased frequency (0.10, p<0.005, Carrier frequency of the %). PMID: 29144512
Curation History
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