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_000277.2(PAH):c.912G>A (p.Gln304=)

CA229845

102892 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 264d0ad0-d6e2-476b-bd24-bbdc8f2ccd05

Approved on: 2019-08-06

Published on: 2019-08-07

HGVS expressions

NM_000277.2:c.912G>A

NM_000277.2(PAH):c.912G>A (p.Gln304=)

NC_000012.12:g.102851687C>T

CM000674.2:g.102851687C>T

NC_000012.11:g.103245465C>T

CM000674.1:g.103245465C>T

NC_000012.10:g.101769595C>T

NG_008690.1:g.70916G>A

NG_008690.2:g.111724G>A

NM_000277.1:c.912G>A

NM_001354304.1:c.912G>A

NM_000277.3:c.912G>A

ENST00000307000.7:c.897G>A

ENST00000549247.6:n.671G>A

ENST00000551114.2:n.574G>A

ENST00000553106.5:c.912G>A

ENST00000635477.1:n.73G>A

Likely Pathogenic

PP3 PP4_Moderate PM3_Strong PM2

Evidence Links 7

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.912G>A (p.Gln304Gln) variant in PAH has been reported in multiple PKU patients (BH4 deficiency excluded in some) (PMID: 23514811). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF=0.000004). This is a synonymous variant that occurs at the junction of exon8/intron8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~20%) the canonical donor site. p.Gln304= has been detected with multiple pathogenic variants without confirmation of parental testing to determine phase: R241H (VarID102804, PMID: 27413125); K363fsdelG (c.1089delG, VarID102518, PMID: 8659548); I65T (VarID636) and A300S (VarID92751, PMID: 2351481); p.R176L (VarID631, PMID: 23500595). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_strong, PP4_moderate.

PP3

Variant at the junction of exon8/intron8 donor splice site. Computation predicts reduction of splicing ~19%.

PP4_Moderate

Detected on 6 alleles of Spanish PKU patients (Table 1) BH4 deficiency ruled out. PMID: 23514811

Detected on 6 alleles (Table 1). Patients with transient HPA (two patients) or with HPA due to a defect in the synthesis or recycling of the cofactor BH4 (two patients) were excluded. PubMed:23514811

Detected in a Spanish PKU cohort; Genotype not indicated. (Table 1) PubMed:7766951

PM3_Strong

Detected with R241H (VarID102804, P). Parental testing not reported. PMID: 27413125. Detected with K363fsdelG (c.1089delG, VarID102518, P/LP) Parental testing not reported. PMID: 8659548. Detected with I65T (VarID636, P) in 2 unrelated patients and A300S (VarID92751, P). Parental confirmation not stated. PMID: 2351481. Detected with p.R176L (VarID631, P) in 1 patient. Parental confirmation not stated. PMID: 23500595

Detected on 2 alleles (table 2, "polymorphism", 2.56% frequency in cohort), once in a patient with genotype c.838G>Ap.E280K/c.838G>Ap.E280K PubMed:26413448

Patient 45: p.Q304Q~p.R176L. Genomic DNA of patients and their families was obtained from 3 mL of EDTA blood sample PubMed:23500595

Found in the homozygous state in 1 patient. Familial segregation analysis was confirmed in 45 of our patients and in three cases both parents were not available. Carrier state was proved in six of nine homozygous patients’ progenitors; however, in two of the three remaining families, the parents were consanguineous. PubMed:24941924

Detected with R241H in subject 6. Parental testing not reported. PubMed:27413125

Patient(s) genotype: p.I65T/p.Q304Q detected in 2 unrelated patients. Patient 48: p.A300S/p.Q304Q. Genomic DNA of patients and their families was obtained from whole blood samples. PubMed:23514811

Table 4, Patient I/1059/ITDE-20, Genotype Q304Q/K363fsdelG. Parental testing not reported. PubMed:8659548

PM2

1 in gnomAD

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