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(PAH):c.688G>A (p.Val230Ile)

CA286506

102784 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 08c0af15-2212-42d9-841c-0a5e84d6838d

HGVS expressions

NM_000277.1:c.688G>A

NM_000277.1(PAH):c.688G>A (p.Val230Ile)

NC_000012.12:g.102855154C>T

CM000674.2:g.102855154C>T

NC_000012.11:g.103248932C>T

CM000674.1:g.103248932C>T

NC_000012.10:g.101773062C>T

NG_008690.1:g.67449G>A

NG_008690.2:g.108257G>A

NM_000277.2:c.688G>A

NM_001354304.1:c.688G>A

NM_000277.3:c.688G>A

ENST00000307000.7:c.673G>A

ENST00000549111.5:n.784G>A

ENST00000553106.5:c.688G>A

Likely Pathogenic

PM3_Very Strong PP4_Moderate

PS3 PP3 PM5 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: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong).

PM3_Very Strong

Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup.

V230I found in 6 patients with PKU: 2 mHPA patients in trans with IVS10-11G>A (varID 607, Pathogenic); 1 mPKU patient in trans with p.L48S (varID 608, Pathogenic); 1 mHPA patient in trans with p.R408W (varID 577, Pathogenic); 1 mHPA patient in trans with p.E390G (varID 625, Pathogenic/LP); 1 mHPA patient in trans with IVS2+5G>C. PubMed:21147011

R158Q/V230I present in one patient with classical PKU (seen with V245V/IVS3nt-22ct/IVS5nt-54a>g); G272X/V230I present in one patient showing HPA phenotype (seen with V245V/E280 > Q280) PubMed:15943553

PP4_Moderate

V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG.

Subjects included 53 unrelated patients presenting with blood phenylalanine levels persistently above 150 umol/l. The criteria for inclusion were: normal serum tyrosine, normal urinary excresion of biopterin and neopterin, and no indication of acquired hyperphenylalaninemia. V230I was found on 1 chromosome. PubMed:8268925

PS3

In vitro studies in 2 expression systems show reduced activity of V230I mutant, 52-72% of wt.

We have used two heterologous in vitro expression systems (a mammalian cell-free transcription-translation system and the pET system of Escherichia coli). V230I showed pcDNA3/IVT: 72;53% of wt and 52% in pET/E. coli. Could not detect any tetrameric forms of enzymes carrying V230I. PubMed:11161839

Reference to residual in vitro activity of V230I mutant with 63% of wt activity. PubMed:17924342

PP3

Conflicting interpretations of pathogenicity (tolerated in SIFT, benign in PolyPhen2, Damaging in MutationTaster

PM5

V230G, no clinical significance provided

PM2

MAF=0.00266 in gnomAD

Approved on: 2018-08-12

Published on: 2019-04-05

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