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_000277.1:c.689T>C

CA16020840

557425 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5c77b53c-39cf-4cb1-8003-f25232414e04

Approved on: 2020-08-07

Published on: 2021-09-26

HGVS expressions

NM_000277.1:c.689T>C

NC_000012.12:g.102855153A>G

CM000674.2:g.102855153A>G

NC_000012.11:g.103248931A>G

CM000674.1:g.103248931A>G

NC_000012.10:g.101773061A>G

NG_008690.1:g.67450T>C

NG_008690.2:g.108258T>C

ENST00000553106.6:c.689T>C

ENST00000307000.7:c.674T>C

ENST00000549111.5:n.785T>C

ENST00000553106.5:c.689T>C

NM_000277.2:c.689T>C

NM_001354304.1:c.689T>C

NM_000277.3:c.689T>C

NM_001354304.2:c.689T>C

Likely Pathogenic

PM3_Strong PP3 PM2 PP4_Moderate

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.689T>C (p.Val230Ala) variant in PAH has been reported in multiple individuals with MHP, mild PKU and classical PKU (BH4 deficiency excluded, PMID: 18299955, 29316886, 30747360). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.V230I, p.A300S, and p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

PM3_Strong

V230A detected with 2 known pathogenic variants (V230I, A300S) in 2 patients. Parental analysis not reported PMID: 18299955. Detected in trans with p.Arg243Gln (P 11 submitters) PMID: 29316886

V230A found in trans with V230I (Var ID 102784, Pathogenic/LP) in 1 patient with MHP, and in trans with A300S (Var ID 92751, Pathogenic) in 1 patient with mild PKU. PubMed:18299955

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

V230A found in 1 MHP patient and 1 mild PKU patient. BH4 deficiency not ruled out. PMID: 18299955 Also found in a patient with mHP (480) PMID: 29316886 and classical PKU (All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples) PMID: 30747360

180 DNA samples (360 independent alleles) were obtained from unrelated patients with PKU. V230A was found in 1 patient with MHP (plasma phenylalanine concentrations of less than 6.5 mg/dl on a normal diet), and 1 patient with mild PKU (plasma phenylalanine concentrations 6.5–10 mg/dl and tolerate 400–600 mg/day of dietary phenylalanine). PubMed:18299955

PM5

V230I (VarID 102784I is LP by PAH VCEP

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.