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.734T>C (p.Val245Ala)

CA114372

632 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0129bef0-6e1d-4f6b-8e4e-2c05721902af

HGVS expressions

NM_000277.2:c.734T>C

NM_000277.2(PAH):c.734T>C (p.Val245Ala)

NC_000012.12:g.102852923A>G

CM000674.2:g.102852923A>G

NC_000012.11:g.103246701A>G

CM000674.1:g.103246701A>G

NC_000012.10:g.101770831A>G

NG_008690.1:g.69680T>C

NG_008690.2:g.110488T>C

NM_000277.1:c.734T>C

NM_001354304.1:c.734T>C

NM_000277.3:c.734T>C

ENST00000307000.7:c.719T>C

ENST00000549247.6:n.493T>C

ENST00000553106.5:c.734T>C

Pathogenic

PM5 PP4_Moderate PM3_Very Strong

PM2 PS3 PP3

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: PM5: V245L Pathogenic; PP4_Moderate: Seen in at least 7 MHP patients. Exclusion of a defect in tetrahydrobiopterin metabolism. Upgraded per ClinGen Metabolic Workgroup. (PMID:7981714; PMID:9298832; PMID:9634518); PM3_VeryStrong: V245A detected with IVS-12nt1, R252W, L194P (both P/LP), R408W (Path). Upgraded per ClinGen SVI Workgroup (PMID:7981714; PMID:9298832; PMID:8088845). 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: (PM5, PP4_Moderate, PM3_VeryStrong).

PM5

V245L Pathogenic

PP4_Moderate

Seen in at least 7 MHP patients. Exclusion of a defect in tetrahydrobiopterin metabolism. Upgraded per ClinGen Metabolic Workgroup.

Seven centers in France, Italy, Belgium, Germany, and Denmark participated in this collaborative study. In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. V245A was seen in 7 MHP patients from 3 different centers. Patients who have phenylalanine levels <600 mmol/liter on a normal diet were classified as having MHP. PubMed:9634518

One non-PKU HPA patient (F) carries two novel mutations. One is a T-to-C transition at codon 245 in exon 7, resulting in the replacement of valine by alanine (V245A). Serum Phe level 237 umol/liter. PubMed:7981714

Genomic DNA was isolated from total blood of 34 MHP and eight mild PKU probands from unrelated Polish families. V245A was detected in 2 patients (serum Phe levels 442, 394). PubMed:9298832

PM3_Very Strong

V245A detected with IVS-12nt1, R252W, L194P (both P/LP), R408W (Path). Upgraded per ClinGen SVI Workgroup

Patient F: V245A/L194P (VarID 102742, P/LP) PubMed:7981714

V245A seen in 2 patients. Once with R252W (varID 584, P/LP). Once with R408W (VarID 577, Pathogenic) PubMed:9298832

Patient K Genotype: V245A/IVS-12nt1. Patient L: V245A/R408W. Patient M: V245A/Y414C PubMed:8088845

PM2

ExAC MAF: 0.00114

PS3

V245A has PAH enzyme activities 63;39 (% of wt). 50% stated in PAHdb/BioPKU

Two heterologous in vitro expression systems (cell-free rabbit reticulocyte lysates) to assess the residual activities and oligomeric compositions. V245A had PAH enzyme activities 63;39 (% of wt, pcDNA3/IVT). PubMed:11161839

PP3

Conflicting predictions of pathogenicity: Tolerated in SIFT, Damaging in Polyphen2, MutationTaster.

Approved on: 2018-09-28

Published on: 2019-04-05

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