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.1139C>T (p.Thr380Met)

CA114369

628 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 95c70134-5e17-4767-a5b4-84155f4374bd

HGVS expressions

NM_000277.1:c.1139C>T

NM_000277.1(PAH):c.1139C>T (p.Thr380Met)

NC_000012.12:g.102843706G>A

CM000674.2:g.102843706G>A

NC_000012.11:g.103237484G>A

CM000674.1:g.103237484G>A

NC_000012.10:g.101761614G>A

NG_008690.1:g.78897C>T

NG_008690.2:g.119705C>T

NM_000277.2:c.1139C>T

NM_001354304.1:c.1139C>T

NM_000277.3:c.1139C>T

ENST00000307000.7:c.1124C>T

ENST00000549247.6:n.898C>T

ENST00000551114.2:n.801C>T

ENST00000553106.5:c.1139C>T

ENST00000635477.1:n.243C>T

ENST00000635528.1:n.654C>T

Pathogenic

PS3 PP3 PP4_Moderate PM3_Very Strong

PM2 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong

PS3

In vitro residual activity of T380M mutant was 28% of wild type. PMID: 27620137

Transient expression of mutant full-length cDNAs in COS-7 cells yielded PAH proteins with PAH activity levels between 7% and 51% compared to the wild-type enzyme. Higher activity correlated with milder phenotypes (e.g. p.T380M with 28% PAH activity) PubMed:27620137

PP3

Deleterious effect predicted by SIFT, PolyPhen2, MutationTaster

PP4_Moderate

T380M found in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. PMID: 8268925

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. T380M was found on 1 chromosome. PubMed:8268925

PM3_Very Strong

Detected in trans with R408W (P), R261Q (P/LP), I65T (P/LP), F299C (P/LP). Upgraded per ClinGen SVI workgroup. PMID: 7981714

In all patients carrying T380M, mutations known to cause classic PKU (R408W, R261Q, I65T, and F299C) were identified on the other chromosome. The mutations identified were confirmed by restriction analysis of PCR products reamplified from genomic DNA in affected subjects and their parents. PubMed:7981714

PM2

MAF=0.00463 in gnomAD

PM5

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

Approved on: 2018-10-01

Published on: 2019-04-05

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