Variant: NM_000277.2(PAH):c.350delC (p.Thr117Lysfs)

CA267653

120274 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: df824c1a-6747-41fc-9fc4-cfd843dfe25e

HGVS expressions

NM_000277.2:c.350delC
NM_000277.2(PAH):c.350delC (p.Thr117Lysfs)
NC_000012.12:g.102894737del
CM000674.2:g.102894737del
NC_000012.11:g.103288515del
CM000674.1:g.103288515del
NC_000012.10:g.101812645del
NG_008690.1:g.27866del
NG_008690.2:g.68674del
NM_000277.1:c.350del
NM_000277.2:c.350del
NM_001354304.1:c.350del
NM_000277.3:c.350del
ENST00000307000.7:c.335del
ENST00000546844.1:c.350del
ENST00000548928.1:n.272del
ENST00000549111.5:n.446del
ENST00000550978.6:n.334del
ENST00000551337.5:c.350del
ENST00000551988.5:n.439del
ENST00000553106.5:c.350del

Pathogenic

• Met criteria codes: PP4 PM2 PVS1

• Not Met criteria codes: PS3 BA1 BS1 BS2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.350delC variant in PAH has been previously reported in at least 2 Arab-Israeli probands with classic PKU (PMID: 18299955; PMID: 18294361); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and the Greater Middle East Variome (PM2).

Met criteria codes

• PP4: Found in at least two probands with classic PKU (PMID: 18294361); also reported in 1 proband with classic PKU (PMID: 18299955); however, the publications are by the same author and published in the same year, and use patients from the same medical center (without any additional patient IDs, etc.), so difficult to tell whether it is 3 different probands or 1 overlaps between the 2 publications. Thus conservatively counting as 2 probands with classic PKU.
• PM2: Absent from 1000G, ExAC/gnomAD, ESP, and the Greater Middle East Variome.
• PVS1: Frameshift variant predicted to lead to premature protein truncation in exon 3 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria).

Not Met criteria codes

• PS3: No in-vitro assays performed for this variant.
• BA1: Absent from 1000G, ExAC/gnomAD, ESP, and the Greater Middle East Variome.
• BS1: Absent from 1000G, ExAC/gnomAD, ESP, and the Greater Middle East Variome.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2018-12-22

Published on: 2019-04-06