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]

x This classification has been retracted/unpublished!

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.194T>C (p.Ile65Thr)

CA251544

636 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 633ef5e6-95c8-4ff5-88b2-6cf22b99158b

Approved on: 2018-04-21

Published on: 2019-04-08

HGVS expressions

NM_000277.2:c.194T>C

NM_000277.2(PAH):c.194T>C (p.Ile65Thr)

NC_000012.12:g.102894893A>G

CM000674.2:g.102894893A>G

NC_000012.11:g.103288671A>G

CM000674.1:g.103288671A>G

NC_000012.10:g.101812801A>G

NG_008690.1:g.27710T>C

NG_008690.2:g.68518T>C

NM_000277.1:c.194T>C

NM_001354304.1:c.194T>C

NM_000277.3:c.194T>C

ENST00000307000.7:c.179T>C

ENST00000546844.1:c.194T>C

ENST00000548677.2:n.281T>C

ENST00000548928.1:n.116T>C

ENST00000549111.5:n.290T>C

ENST00000550978.6:n.178T>C

ENST00000551337.5:c.194T>C

ENST00000551988.5:n.283T>C

ENST00000553106.5:c.194T>C

ENST00000635500.1:n.162T>C

Pathogenic

PM3_Very Strong PP4_Moderate PS3 PP3

PS1 PP1 PM2 PM5

Evidence Links 4

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: PM3_VeryStrong: Detected with Y414C (P), R408W (P), P281L (P), IVS10nt-11 (P), R252W (P/LP), and R243Q(P). (PMID:12501224; PMID:1301201; PMID:10767174); PP3: Predicted dleterious in SIZFT, Polyphen2, MutationTaster. REVEL=0.985; PP4_Moderate: Detected in a patient with mild PKU. BH4 deficiency excluded. Upgraded per ClinGen PAH EP. (PMID:12501224); PS3: 25% mutant enzyme activity in COS cells as compared in wt (PMID:1301201). 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: (PM3_VeryStrong, PP3, PP4_Moderate, PS3).

PM3_Very Strong

Detected with Y414C (P), R408W (P), P281L (P), IVS10nt-11 (P), R252W (P/LP), and R243Q(P).

F13 and G3: I65T/P281L; G21: I65T/IVS10nt-11; G62: I65T/R252W; F38: I65T/I65T; F27: I65T/R243Q. PubMed:10767174

We amplified and sequenced exon 3 from a PKU proband harboring the R408W allele on the other chromosome (see John et al., 1990, family #6). We identified a T to C transition in codon 65 (Fig. 1A). This substitution changes an isoleucine codon (ATT) to one for threonine (ACT); no other changes were found in the entire coding region or in the exon intron boundaries of the PAH gene. The I65T mutation, segregated with this haplotype in the nuclear family (Fig. 1B). PubMed:1301201

Patient 24 Genotype: I65T/Y414C PubMed:12501224

PP4_Moderate

Detected in a patient with mild PKU. BH4 deficiency excluded. Upgraded per ClinGen PAH EP.

38 children with various classes of hyperphenylalaninemia stratified according to the plasma phenylalanine concentration before treatment (normal, 30 to 120 μmol per liter). A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. Patient 24 had mild PKU, and I65T. PubMed:12501224

PS3

25% mutant enzyme activity in COS cells as compared in wt

expression analysis of the I65T mutation in COS cells demonstrating 75% loss of both immunoreactive protein and enzyme activity PubMed:1301201

PP3

Predicted dleterious in SIZFT, Polyphen2, MutationTaster. REVEL=0.985

PS1

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

PP1

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

PM2

gnomAD MAF: 0.00058

The. c.194T>C (p.I65T) variant was identified in a homozygous state in patients with hyperphenylalaninemia (HPA) in a study of 83 individuals from the Southern region of Portugal. PubMed:21871829

PM5

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

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