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_000277.1(PAH):c.1066-11G>A

CA251538

607 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 2470a255-3083-4956-9ff7-176203d54920

HGVS expressions

NM_000277.1:c.1066-11G>A
NM_000277.1(PAH):c.1066-11G>A
NC_000012.12:g.102843790C>T
CM000674.2:g.102843790C>T
NC_000012.11:g.103237568C>T
CM000674.1:g.103237568C>T
NC_000012.10:g.101761698C>T
NG_008690.1:g.78813G>A
NG_008690.2:g.119621G>A
NM_000277.2:c.1066-11G>A
NM_001354304.1:c.1066-11G>A
NM_000277.3:c.1066-11G>A
ENST00000307000.7:c.1051-11G>A
ENST00000549247.6:n.825-11G>A
ENST00000551114.2:n.728-11G>A
ENST00000553106.5:c.1066-11G>A
ENST00000635477.1:n.170-11G>A
ENST00000635528.1:n.581-11G>A

Pathogenic

Met criteria codes 4
PM3_Strong PP4_Moderate PS3 PP3
Not Met criteria codes 2
PM2 PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.1066-11G>A variant in PAH has been reported in > 76 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 23500595; PMID: 8990013). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with multiple known pathogenic variants: p.R243Q, p.R243X, p.R261Q, p.R270K, p.I65T. (PM3_Strong; PMID: 23500595; PMID: 8990013). Computational prediction tools and conservation analysis suggest that the c.1066-11G>A variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong
Met criteria codes
PM3_Strong
Detected with: p.R243Q (P); p.R243X (P); p.R261Q (P/LP); p.R270K (P); p.I65T (P/LP). PMID: 23500595; PMID: 8990013.

PP4_Moderate
IVS10-11G>A seen in > 76 PKU alleles. BH4 deficiency ruled out in 1 study with 29 alleles. Upgraded per ClinGen Metabolic workgroup

PS3
In vitro functional studies support a damaging effect on the gene (alternative splicing) and gene product (no PAH activity)

PP3
Predicted in affect splicing in HSF and MaxEnt. Conserved in 25/31 vertebrates.
Not Met criteria codes
PM2
Does not meet PAH EP PM2 cutoff (<0.0002): MAF in 1000G EUR, AF=0.00298 (3/1006); 0.0002424 in gnomAD
PM5
Current variant is in non-coding region
Approved on: 2018-10-01
Published on: 2019-04-05
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