The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Criteria Specification: CSpec Registry PDF

Variant: NM_000277.3(PAH):c.722del (p.Arg241fs)

CA229717

102806 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 0bdb972a-5443-41f0-83ef-c13fe30cfde1

HGVS expressions

NM_000277.3:c.722del
NM_000277.3(PAH):c.722del (p.Arg241fs)
NM_000277.1:c.722del
NM_000277.2:c.722del
NM_001354304.1:c.722del
NM_001354304.2:c.722del
ENST00000307000.7:c.707del
ENST00000549247.6:n.481del
ENST00000553106.5:c.722del
NC_000012.12:g.102852935del
CM000674.2:g.102852935del
NC_000012.11:g.103246713del
CM000674.1:g.103246713del
NC_000012.10:g.101770843del
NG_008690.1:g.69668del
NG_008690.2:g.110476del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM3_Very Strong PVS1 PP4_Moderate PM2

Evidence Links 2

Evidence submitted by expert panel
Phenylketonuria VCEP
The PAH variant c.722del (p.Arg241fs) is a null variant (frameshift indel) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The mRNA transcript is predicted to undergo NMD. The PAH variant c.722del (p.Arg241fs) was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10–20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PMID: 26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612)(PMID: 30459323). PM3_Very Strong (6.75). The variant c.722del (p.Arg241fs) is absent from the gnomAD, and ExAC population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong (6.75), PVS1, PP4_Moderate.
Met criteria codes
PM3_Very Strong
The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 5) (PMID: 26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 1.75)(PMID: 30459323). PM3_Very Strong (6.75)

PVS1
According to Franklin, the variant p.R241Pfs*100 is a null variant (frameshift indel). The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The coding strand: reverse strand. This variant is not located in the last exon or the last 50bp of the preliminary exon, and therefore the mRNA transcript is predicted to undergo NMD. The variant is located in coding exon number 7 out of 13 coding exons.
PP4_Moderate
The variant p.R241Pfs*100 was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10–20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415)
PM2
The PAH variant p.R241Pfs*100 is absent from the gnomAD, and ExAC population databases.
Approved on: 2020-05-09
Published on: 2020-05-09
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