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Variant: NM_000277.2(PAH):c.1301C>A (p.Ala434Asp)

CA229427

102586 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: d30a56d8-d14c-492c-afea-2eaecad4b3f1
Approved on: 2023-12-30
Published on: 2023-12-30

HGVS expressions

NM_000277.2:c.1301C>A
NM_000277.2(PAH):c.1301C>A (p.Ala434Asp)
NC_000012.12:g.102840414G>T
CM000674.2:g.102840414G>T
NC_000012.11:g.103234192G>T
CM000674.1:g.103234192G>T
NC_000012.10:g.101758322G>T
NG_008690.1:g.82189C>A
NG_008690.2:g.122997C>A
ENST00000553106.6:c.1301C>A
ENST00000307000.7:c.1286C>A
ENST00000551114.2:n.963C>A
ENST00000553106.5:c.1301C>A
ENST00000635477.1:c.405C>A
ENST00000635528.1:n.816C>A
NM_000277.1:c.1301C>A
NM_001354304.1:c.1301C>A
NM_000277.3:c.1301C>A
NM_001354304.2:c.1301C>A
NM_000277.3(PAH):c.1301C>A (p.Ala434Asp)
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Pathogenic

Met criteria codes 5
PS3_Supporting PM2_Supporting PP4_Moderate PM3_Very Strong PP3
Not Met criteria codes 1
PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3.
Met criteria codes
PS3_Supporting
Residual enzyme activity of A434D mutant is 21.7% of wild type. A434D affected the formation and stability of the PAH protein. PMID: 18247293

PM2_Supporting
Absent from ExAC, gnomAD, 1000G, and ESP
PP4_Moderate
A434D seen in 5 patients with classical & mild PKU and PAH deficiency. BH4 deficiency was ruled out in 2 patients by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 16256386, PMID: 21147011

PM3_Very Strong
A434D seen with known pathogenic variants R252Q, R243Q. parental analysis when available PMID: 16256386; p.E390G (P 9 submitters), p.R261Q (P 11 submitters) parental analysis not reported PMID: 21147011; R243Q (3 patients); IVS4-1G>A (2 patients, P 5 submitters); E280K (P 9 submitters), R111X (P 6 submitters) parental analysis not reported PMID: 23932990

PP3
Deleterious effect predicted in SIFT, Polyphen2, MutationTaster, REVEL=0.966
Not Met criteria codes
PM5
Only variant in this codon
Curation History
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