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: 2024-11-17

Published on: 2024-11-18

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

Pathogenic

• Met criteria codes: PP4_Moderate PM3_Very Strong PM2_Supporting PP3

• Not Met criteria codes: BP7

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3: c.441+5G>A variant in PAH is an intronic variant that is predicted by SpliceAI to alter splicing (SpliceAI score 0.91, >0.2 cutoff for PP3). c.441+5G>A has a Pop max allele frequency of [8.498e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. It has been observed in individuals with phenylalanine hydroxylase deficiency in presumed trans (phase confirmed) with other pathogenic variants, including with p.Arg158Gln (ClinVar ID: 587) in one individual (PMID: 18321666) and with p.Val388Met (ClinVar ID 619) in 8 individuals (PMID: 32668217) (PM3_VeryStrong). It has been observed in at least one classic PKU patient with BH4 deficiency excluded (PMID: 18321666; PP4_moderate). 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: PM2_Supporting, PM3_VeryStrong, PP3, PP4_Moderate.

Met criteria codes

• 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_Very Strong: NL patient 3 of PMID: 18321666 is compound heterozygous for c.441+5G>A and R158Q (ClinVar 587, Pathogenic reviewed by VCEP). Also reported in 8 patients with genotype p.Val388Met /c.441+5G>A, p.V388M is path in ClinVar (ID 619), phase not confirmed (4pts) (PMID: 32668217). Confirmation of phase not reported.
• PM2_Supporting: c.441+5G>A has a Pop max allele frequency of [8.498e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting.
• PP3: SpliceAI score 0.91, >0.2 cutoff for PP3

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).