Variant: NM_000277.3(PAH):c.558_559del (p.Trp187fs)

CA229621

102734 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 4b62ebbc-50ff-4de2-895c-22dd2c11431d

Approved on: 2020-10-30

Published on: 2020-10-30

HGVS expressions

NM_000277.3:c.558_559del
NM_000277.3(PAH):c.558_559del (p.Trp187fs)
NM_000277.1:c.558_559del
NM_000277.2:c.558_559del
NM_001354304.1:c.558_559del
NM_001354304.2:c.558_559del
ENST00000307000.7:c.543_544del
ENST00000549111.5:n.654_655del
ENST00000551988.5:n.579_580del
ENST00000553106.5:c.558_559del
NC_000012.12:g.102855283_102855284del
CM000674.2:g.102855283_102855284del
NC_000012.11:g.103249061_103249062del
CM000674.1:g.103249061_103249062del
NC_000012.10:g.101773191_101773192del
NG_008690.1:g.67319_67320del
NG_008690.2:g.108127_108128del

Pathogenic

• Met criteria codes: PVS1 PM3_Supporting PP4 PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.558_559del (p.Trp187fs) variant in PAH has been reported in 1 Indian PKU patient; Phe = 1240umol/L; BH4 deficiency not excluded (PMID: 24130151; PP4). The variant was detected in the homozygous state, both parents confirmed to be heterozygous (consanguineous) - 0.5 points (PMID: 24130151; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 6 out of 13 coding exons; 6 out of total exons) (PVS1). This variant was reported in gnomad with MAF = 0.00016 in South Asian population (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting.

Met criteria codes

• PVS1: Frameshift variant, predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 6 out of 13 coding exons (6 out of total exons).
• PM3_Supporting: PMID: 24130151 - W187fs detected in homozygous state, both parents confirmed to be heterozygous (consanguineous) - 0.5 points
• PP4: PMID: 24130151 - W187fs detected in 1 Indian PKU patient; Phe = 1240umol/L; BH4 deficiency not excluded
• PM2: gnomAD MAF = 0.00016 in South Asian population.