Variant: NM_000277.3(PAH):c.241_256del (p.Thr81fs)

CA229499

102638 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 9c0824e1-2710-46f7-8a21-a59b73ada7a0

Approved on: 2020-10-22

Published on: 2020-10-22

HGVS expressions

NM_000277.3:c.241_256del
NM_000277.3(PAH):c.241_256del (p.Thr81fs)
NM_000277.1:c.241_256del
NM_000277.2:c.241_256del
NM_001354304.1:c.241_256del
NM_001354304.2:c.241_256del
ENST00000307000.7:c.226_241del
ENST00000546844.1:c.241_256del
ENST00000548677.2:n.328_343del
ENST00000548928.1:n.163_178del
ENST00000549111.5:n.337_352del
ENST00000550978.6:n.225_240del
ENST00000551337.5:c.241_256del
ENST00000551988.5:n.330_345del
ENST00000553106.5:c.241_256del
NC_000012.12:g.102894832_102894847del
CM000674.2:g.102894832_102894847del
NC_000012.11:g.103288610_103288625del
CM000674.1:g.103288610_103288625del
NC_000012.10:g.101812740_101812755del
NG_008690.1:g.27757_27772del
NG_008690.2:g.68565_68580del

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM3 PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.241_256del (p.Thr81fs) variant in PAH has been reported in two patients with PKU, observed with two pathogenic variants: p.R241C, phase unknown (PMID: 14722928) and with p.V399V, phase unknown (PMID: 24401910). This variant is absent from controls is population databases. This is a frameshift variant in exon 3 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate, and PM3.

Met criteria codes

• PVS1: This is a frameshift variant in exon 3 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. Loss of function is a known mechanism of disease: 175 pathogenic null variants reported in Clinvar across 13 different exons, 20 of which are in exon 3.
• PP4_Moderate: Observed in a patient with mild PKU (Phe = 851 µmol/L). 6R-BH4 was ruled out based on analyses of urinary pterins, dihydropteridine reductase activity in erythrocytes, and PTPS gene mutation. PMID: 14722928
• PM3: [p.T81_R86>VfsX6; p.V399V]. When sequence alteration was identified, paternal or maternal origin was determined whenever the parental DNA was available. PMID: 24401910. p.[T81fsX6; R241C]. Segregation analysis was not done, so phase is unknown. PMID: 14722928
• PM2: This variant is absent from controls in gnomAD and ExAC.