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Variant: NM_000277.1(PAH):c.721C>T (p.Arg241Cys)

CA273357

102803 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: dd8fcc3c-dde1-42d4-a0f2-31bbafa786a5

HGVS expressions

NM_000277.1:c.721C>T
NM_000277.1(PAH):c.721C>T (p.Arg241Cys)
NC_000012.12:g.102852936G>A
CM000674.2:g.102852936G>A
NC_000012.11:g.103246714G>A
CM000674.1:g.103246714G>A
NC_000012.10:g.101770844G>A
NG_008690.1:g.69667C>T
NG_008690.2:g.110475C>T
NM_000277.2:c.721C>T
NM_001354304.1:c.721C>T
NM_000277.3:c.721C>T
ENST00000307000.7:c.706C>T
ENST00000549247.6:n.480C>T
ENST00000553106.5:c.721C>T

Pathogenic

Met criteria codes 5
PM3_Strong PS3 PP4_Moderate PP3 PM2
Not Met criteria codes 1
PM5

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong, PS3).
Met criteria codes
PM3_Strong
R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup.

PS3
In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote.

PP4_Moderate
Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup.

PP3
Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster
PM2
Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301)
Not Met criteria codes
PM5
R241H (VarID 102804) is Pathogenic in ClinVar based on 3 submitters
Approved on: 2018-08-10
Published on: 2019-04-05
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