Evidence Repository - Clinical Genome Resources

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

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

CA229717

102806 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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"

PVS1 PM3_Very Strong PM2 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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.

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)

PubMed:30459323

PubMed:26322415

PM2

The PAH variant p.R241Pfs*100 is absent from the gnomAD, and ExAC population databases.

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)

Approved on: 2020-05-09

Published on: 2020-05-09

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