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_000277.2(PAH):c.441+6T>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA267654

120275 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f4d1a114-f822-49f7-aec3-f445c0174a02

Approved on: 2019-08-06

Published on: 2019-08-07

HGVS expressions

NM_000277.2:c.441+6T>A

NM_000277.2(PAH):c.441+6T>A

NC_000012.12:g.102877456A>T

CM000674.2:g.102877456A>T

NC_000012.11:g.103271234A>T

CM000674.1:g.103271234A>T

NC_000012.10:g.101795364A>T

NG_008690.1:g.45147T>A

NG_008690.2:g.85955T>A

NM_000277.1:c.441+6T>A

NM_001354304.1:c.441+6T>A

NM_000277.3:c.441+6T>A

ENST00000307000.7:c.426+6T>A

ENST00000549111.5:n.537+6T>A

ENST00000550978.6:n.431T>A

ENST00000551988.5:n.530+6T>A

ENST00000553106.5:c.441+6T>A

Likely Pathogenic

PP4_Moderate PM3_Strong PM2 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+6T>A variant in PAH has been reported in at least 2 patients with PKU (BH4 deficiency ruled out), who carried pathogenic variants (ClinVar IDs: 589 & 576) (PMID: 22526846). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF= 0.000004). This intronic variant changes a moderately conserved nucleotide, and computational analyses (Alamut) predict that this variant may weaken (~60%) the splice donor site of intron 4. Based on the available information, this variant is considered to be likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PP4_M, PM2, PM3_S.

PP4_Moderate

Patient 95: BH4 deficiency ruled out; Phe 900 uM. (Supplemental table 1)

Patient 95: BH4 deficiency ruled out; Phe 900 uM. (Supplemental table 1) PubMed:22526846

PM3_Strong

Detected in trans with likely pathogenic p.P281L (ClinVar 589) family segregation performed, and c.1315+1G>A (ClinVar 576).

Detected in trans with likely pathogenic p.P281L (ClinVar 589), and c.1315+1G>A (ClinVar 576). Family segregation was consistent with autosomal recessive inheritance. PubMed:22526846

PM2

gnomAD MAF 0.000004

PP3

Alamut predictors: reduces ~60% the donor site of exon 4/intron 4.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.