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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.473G>A (p.Arg158Gln)

CA251530

587 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0c42e06b-e66b-4820-b77e-007dbe8b7c6f

HGVS expressions

NM_000277.2:c.473G>A

NM_000277.2(PAH):c.473G>A (p.Arg158Gln)

NC_000012.12:g.102866632C>T

CM000674.2:g.102866632C>T

NC_000012.11:g.103260410C>T

CM000674.1:g.103260410C>T

NC_000012.10:g.101784540C>T

NG_008690.1:g.55971G>A

NG_008690.2:g.96779G>A

NM_000277.1:c.473G>A

NM_001354304.1:c.473G>A

NM_000277.3:c.473G>A

ENST00000307000.7:c.458G>A

ENST00000549111.5:n.569G>A

ENST00000551988.5:n.530+10830G>A

ENST00000553106.5:c.473G>A

Pathogenic

PS3 PP3 PP4_Moderate PM3_Very Strong

PS2 PM2

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). 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: (PS3, PP3, PP4_Moderate, PM3_VeryStrong).

PS3

R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type.

Expression studies found that R158Q is associated with very low levels (0.2-1.8%) of phenylalanine hydroxylase enzyme activity compared to wild-type (Comments per Jaimie Higgs). Several PAH variants were introduced into constructs and expressed in E. coli, and enzyme activity was measured using both Phenylalanine and SCMC as substrates. R158Q PAH had <2% of PAH activity compared to wildtype when Phe was used as substrate and <0.1% when SCMC was used as substrate. PubMed:19036622

PAH variants previously identified in patients were introduced into PAH cDNA by site-directed mutagenesis, subcloned into expression vectors and transfected into monkey kidney COS cells; PAH mRNA expression, enzyme activity and immunoreactivity were measured in cellular extracts; R158Q had enzyme activity approximately 10% of WT but had normal immunoreactivity indicating the mutant protein was expressed at normal levels but specific activity is reduced PubMed:2014036

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4_Moderate

BH4 testing showed responsive in a pt, pretreatment 1065uM

in vitro enzyme activity in this study_1.7-29% of WT; BH4 testing showed responsive in a pt Phe level dropped 43% from pretreatment 1065uM (table 2) ; PubMed:23500595

PM3_Very Strong

in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter.

Patient genotype: G218V (interpretation not provided) /R158Q PubMed:10479481

Patient 5, 38: R158Q/ c.1315+1G>A (VarID576, Pathogenic). Patient 75: R158Q/ p.P281L (VarID 589, Pathogenic). Patient 98: R158Q/ p.R261* (VarID 610, Pathogenic). PubMed:24368688

in trans with p.I48S PubMed:23500595

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2018-08-05

Published on: 2019-04-05

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