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]

Variant: NM_000277.3(PAH):c.1199G>C (p.Arg400Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229391

102562 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f88f0c21-1bca-454f-bb60-cf713e8be790

Approved on: 2020-06-05

Published on: 2021-06-09

HGVS expressions

NM_000277.3:c.1199G>C

NM_000277.3(PAH):c.1199G>C (p.Arg400Thr)

NC_000012.12:g.102843646C>G

CM000674.2:g.102843646C>G

NC_000012.11:g.103237424C>G

CM000674.1:g.103237424C>G

NC_000012.10:g.101761554C>G

NG_008690.1:g.78957G>C

NG_008690.2:g.119765G>C

ENST00000553106.6:c.1199G>C

ENST00000307000.7:c.1184G>C

ENST00000549247.6:n.958G>C

ENST00000551114.2:n.861G>C

ENST00000553106.5:c.1199G>C

ENST00000635477.1:n.303G>C

ENST00000635528.1:n.714G>C

NM_000277.1:c.1199G>C

NM_000277.2:c.1199G>C

NM_001354304.1:c.1199G>C

NM_001354304.2:c.1199G>C

Pathogenic

PM3_Very Strong PP4_Moderate PM2

PP3 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.1199G>C (p.Arg400Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 16256386, 19915519, 23932990). This variant is absent in population databases. It has been detected with pathogenic variants: IVS7+2T>A, p.R243Q, p.G346R (PMID: 16256386); and in trans with IVS4+3G＞C, p.His107Arg, EX6-96A＞G, p.Arg243Gln, IVS4-1G＞A (PMID: 29316886). Computational prediction tools and conservation analysis are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate.

PM3_Very Strong

detected with IVS7+2T>A (P 1 submitter), R243Q (pathogenic), and G346R (pathogenic) parental analysis not confirmed PMID: 16256386. in trans with F263L (US, parental analysis performed) PMID: 26600521 IVS4+3G＞C (P/LP 2 submitters), p.His107Arg (P/LP 4 submitters), EX6-96A＞G (P 6 submitters), p.Arg243Gln (P 11 submitters), IVS4-1G＞A (P 4 submitters) PMID: 29316886 (6.75 pts)

Seen in 3 individuals with classic PKU (PHE > 1200 umol/L), in trans with IVS7+2T>A, R243Q (pathogenic), and G346R (pathogenic) PubMed:16256386

PP4_Moderate

Seen in multiple individuals with PKU. PMID: 16256386, 19915519 A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 23932990

Seen in an individual with PKU, identified in neonatal screening. PubMed:19915519

Seen in multiple individuals with PKU, BH4 deficiency excluded. PubMed:23932990

Seen in 3 individuals with classic PKU (PHE > 1200 umol/L), in trans with IVS7+2T>A, R243Q, and G346R PubMed:16256386

PM2

Absent from controls.

PP3

Predicted damaging by sift and mutation taster. but benign by polyphen.

PM5

R400K curated as LP

Curation History

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