Variant: NM_000277.3:c.1315+5G>C

CA16020995

872836 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 6f43b73e-a3ab-4c22-8a41-b6e84e007afd

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.1315+5G>C
NC_000012.12:g.102840395C>G
CM000674.2:g.102840395C>G
NC_000012.11:g.103234173C>G
CM000674.1:g.103234173C>G
NC_000012.10:g.101758303C>G
NG_008690.1:g.82208G>C
NG_008690.2:g.123016G>C
ENST00000553106.6:c.1315+5G>C
ENST00000307000.7:c.1300+5G>C
ENST00000551114.2:n.977+5G>C
ENST00000553106.5:c.1315+5G>C
ENST00000635477.1:c.419+5G>C
ENST00000635528.1:n.830+5G>C
NM_000277.1:c.1315+5G>C
NM_000277.2:c.1315+5G>C
NM_001354304.1:c.1315+5G>C
NM_001354304.2:c.1315+5G>C

Likely Pathogenic

• Met criteria codes: PP3 PM3 PM2_Supporting PP4_Moderate

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 c.1315+5G>C variant in PAH is an intronic variant in intron 12 that is predicted by multiple splicing tools to alter splicing (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). It has been observed in at least 2 moderate or classic PKU patients with BH4 deficiency excluded (PMID: 30747360, PMID: 33980295; PP4_moderate), including 1 case who harbored it in trans (parental genetic analysis reportedly done for all cases) with the known pathogenic variant p.Arg252Gln (ClinVar ID 102824) (PM3_Moderate). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Moderate, PP4_Moderate, PP3_Supporting.

Met criteria codes

• PP3: Multiple lines of computation evidence agree that there is alteration of the WT donor site, most probably affecting splicing. Human splice finder predicts alteration of WT donor site with -14.36% variation, MaxEnt Scan predicts -80.83% variation, SpliceAI 0.93 for donor loss.
• PM3: PMID: 33980295: 1 case, genotype p.Arg252Gln/ c.1315 + 5G > C. Classic PKU (plasma Phe > 1200), BH4 deficiency excluded by urinary pterin profile analysis, DHPR activity assay, and variant analysis. Parental testing said to be done for all cases for variant phasing. Given potential overlap with PMID: 30747360, counted only for PM3. p.Arg252Gln is path by PAH VCEP (ClinVar ID 102824), thus give 1pt (PM3_Moderate)
• PM2_Supporting: Absent in gnomAD v2.1.1
• PP4_Moderate: (PMID: 30747360) Three c.1315+5G>A alleles were identified; 2 in classic PKU case(s) (Phe ≥ 1200 μmol/L) and one in a moderate case (Phe: 360 ~ 1200 μmol/L). For all patients tetrahydrobiopterin deficiency was excluded through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples.