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_000277.2(PAH):c.441+4A>G

CA229548

102674 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1f6f3246-d55f-4bd2-9d99-b91af935bb51

HGVS expressions

NM_000277.2:c.441+4A>G

NM_000277.2(PAH):c.441+4A>G

NC_000012.12:g.102877458T>C

CM000674.2:g.102877458T>C

NC_000012.11:g.103271236T>C

CM000674.1:g.103271236T>C

NC_000012.10:g.101795366T>C

NG_008690.1:g.45145A>G

NG_008690.2:g.85953A>G

NM_000277.1:c.441+4A>G

NM_001354304.1:c.441+4A>G

NM_000277.3:c.441+4A>G

ENST00000307000.7:c.426+4A>G

ENST00000549111.5:n.537+4A>G

ENST00000550978.6:n.429A>G

ENST00000551988.5:n.530+4A>G

ENST00000553106.5:c.441+4A>G

Uncertain Significance

PP4 PP3 PM2 PM3_Supporting

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+4A>G variant in PAH has been reported in an individual with PAH deficiency (PP4) with likely pathogenic variant p.Val230Ile (PM3-supporting) (PMID: 12655553); and an Iranian patient with PAH deficiency ( PMID: 28676969, 2nd variant not reported). This variant is absent in population databases (PM2). Computational evidence support a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3.

PP4

Detected in a German patient (PMID: 12655553) and an Iranian patient with PAH deficiency ( PMID: 28676969). BH4 deficiency not assessed/reported.

IVS4+4A>G was found on 1/348 German chromosomes. PubMed:12655553

Detected in 1 allele. Eighty-one unrelated Iranian families with PAH deficiency from different regions of the country were recruited to this study. PubMed:28676969

PP3

Broken WT Donor Site in HSF (Alteration of the WT donor site, most probably affecting splicing) and MaxENT (-81%).

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

PM3_Supporting

Detected with p.Val230Ile (VarID 102784, LP). Parental confirmation not reported.

In the EQA scheme, three DNA samples with previously characterized genotypes were sent to each participant along with mock clinical descriptions. 2005, Patient 2, Comp. het.: IVS4+4A>G (c.441+4G>A) and p.Val230Ile (c.688G>A). Parental confirmation not reported. PubMed:19015950

Approved on: 2019-09-29

Published on: 2019-09-29

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.