Variant: NM_001354304.2:c.441+5G>A

CA16020788

987910 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: a88497a0-043d-48a7-8d68-1d6d90f282f4

Approved on: 2020-09-12

Published on: 2020-09-12

HGVS expressions

NM_001354304.2:c.441+5G>A
NC_000012.12:g.102877457C>T
CM000674.2:g.102877457C>T
NC_000012.11:g.103271235C>T
CM000674.1:g.103271235C>T
NC_000012.10:g.101795365C>T
NG_008690.1:g.45146G>A
NG_008690.2:g.85954G>A
ENST00000553106.6:c.441+5G>A
ENST00000307000.7:c.426+5G>A
ENST00000549111.5:n.537+5G>A
ENST00000550978.6:c.430G>A
ENST00000551988.5:n.530+5G>A
ENST00000553106.5:c.441+5G>A
NM_000277.1:c.441+5G>A
NM_000277.2:c.441+5G>A
NM_001354304.1:c.441+5G>A
NM_000277.3:c.441+5G>A

Uncertain Significance

• Met criteria codes: PM2 PP4_Moderate PM3_Supporting

• Not Met criteria codes: BP7

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+5G>A variant in PAH is absent from population databases (PM2). It has been observed in at least one classic PKU patient with BH4 deficiency excluded (PMID: 18321666; PP4_moderate). The patient is compound heterozygous with pathogenic variant R158Q (ClinVar 587; PM3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4_moderate.

Met criteria codes

• PM2: c.441+5G>A is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.
• PP4_Moderate: NL patient 3 of PMID: 18321666 has classic PKU with serum Phe levels of 2388uM. BH4 deficiency was excluded by urine analysis for putative abnormalities in biopterin metabolism.
• PM3_Supporting: NL patient 3 of PMID: 18321666 is compound heterozygous for c.441+5G>A and R158Q (ClinVar 587, Pathogenic reviewed by VCEP). Confirmation of phase not reported.

Not Met criteria codes

• BP7: HSF and MaxEntScan agree that there is no significant impact on splicing signals. However the nucleotide is highly conserved throughout vertebrates (PhyloP score 7.24).