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_000277.1(PAH):c.1066-3C>T

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229324

623 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5fdcac0d-7ea8-4beb-bec5-bc97c75be7af

Approved on: 2023-12-30

Published on: 2023-12-30

HGVS expressions

NM_000277.1:c.1066-3C>T

NM_000277.1(PAH):c.1066-3C>T

NC_000012.12:g.102843782G>A

CM000674.2:g.102843782G>A

NC_000012.11:g.103237560G>A

CM000674.1:g.103237560G>A

NC_000012.10:g.101761690G>A

NG_008690.1:g.78821C>T

NG_008690.2:g.119629C>T

ENST00000553106.6:c.1066-3C>T

ENST00000307000.7:c.1051-3C>T

ENST00000549247.6:n.825-3C>T

ENST00000551114.2:n.728-3C>T

ENST00000553106.5:c.1066-3C>T

ENST00000635477.1:c.170-3C>T

ENST00000635528.1:n.581-3C>T

NM_000277.2:c.1066-3C>T

NM_001354304.1:c.1066-3C>T

NM_000277.3:c.1066-3C>T

NM_001354304.2:c.1066-3C>T

NM_000277.3(PAH):c.1066-3C>T

Pathogenic

PM3_Very Strong PM2_Supporting PP4_Moderate

PS3 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1066-3C>T variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 9634518, 27121329). It has been detected with multiple pathogenic variants: c.1222C>T (p.Arg408Trp) (in trans, PMID: 27121329); c.1315+1G>A (PMID: 17502162); p.G272X, p.S310F (PMID: 23430918); c.194T>C (p.I65T), c.1208C>T (p.A403V), c.398_401del (p.N133fs), c.1222C>T (p.R408W) 2 patients, c.165delT (p.F55fs), c.168+5G>C (IVS2+5G>C) (PMID: 22526846). This variant has an extremely low allele frequency in ExAC and gnomAD (MAF=0.00014). This variant has 0% enzyme activity. This variant resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (PMID: 8098245). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PM2_supporting.

PM3_Very Strong

(c.1066-3C>T)/c.1222C>T (p.Arg408Trp) (P 14 submitters) Segregation analysis was done PMID: 27121329 c.1315+1G>A (P 14 submitters) PMID: 17502162 p.G272X (P 6 submitters) and p.S310F (P 1 submitter) PMID: 23430918 c.194T>C (p.I65T) P 10 submitters; c.1208C>T (p.A403V) P 16 submitters; c.398_401del (p.N133fs) P 2 submitters; c.1222C>T (p.R408W) 2 patients; c.165delT (p.F55fs) P 7 submitters; c.168+5G>C (IVS2+5G>C) P 6 submitters PMID: 22526846 parental analysis not reported

PM2_Supporting

extremely low frequency in ExAC and gnomAD (MAF=0.00014)

PP4_Moderate

PMID 9634518: BH4 deficiency excluded. this splice variant was reported in 2 patients and classified as classic PKU variants in Appendix. PMID: 27121329 A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity.

PS3

PMID 8098245: C to T transition in the splice acceptor site of intron 10 resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (-3 IVS10).

PMID 8098245: One mutation, detected by the abnormal pattern of migration of an amplified fragment, is a C to T transition in the splice acceptor site of intron 10, which resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (-3 IVS10). PubMed:8098245

PP3

Splicing predictions at nearest natural junction. Predicted change at acceptor site 3 bps downstream: -13.5%, MaxEnt: -33.4%, NNSPLICE: 2.3%, HSF: -9.4% ©Interactive Biosoftware - Created by Alamut Visual v.2.9.0 on 7/14/2017

Curation History

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