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]

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Variant: NM_000277.1(PAH):c.441+5G>T

CA273112

92742 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 674e662c-0350-403f-afef-a3cb5a47ced4

HGVS expressions

NM_000277.1:c.441+5G>T

NM_000277.1(PAH):c.441+5G>T

NC_000012.12:g.102877457C>A

CM000674.2:g.102877457C>A

NC_000012.11:g.103271235C>A

CM000674.1:g.103271235C>A

NC_000012.10:g.101795365C>A

NG_008690.1:g.45146G>T

NG_008690.2:g.85954G>T

NM_000277.2:c.441+5G>T

NM_001354304.1:c.441+5G>T

NM_000277.3:c.441+5G>T

ENST00000307000.7:c.426+5G>T

ENST00000549111.5:n.537+5G>T

ENST00000550978.6:n.430G>T

ENST00000551988.5:n.530+5G>T

ENST00000553106.5:c.441+5G>T

Pathogenic

PS3 PP4_Moderate PP3 PM2 PM3_Strong

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>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_Strong

PS3

0 enzyme activity in BioPKU

PP4_Moderate

c.441+5G>T seen on 5 PKU alleles. BH4 deficiency ruled out in 17 alleles. Upgraded per ClinGen PAHEP PMID: 17935162; PMID: 23514811

Data from 315 patients who responded to the BH4 loading test (10–20mg/kg) by lowering their blood phenylalanine levels by 430% after 8 to 24hr, were tabulated in the International Database of Patients and Mutations Causing BH4-Responsive HPA/PKU (BIOPKUdb). c.44115G>T was found on 5 alleles. PubMed:17935162

147 patients (among them seven pairs of siblings) were included. Patients with transient HPA (two patients) or with HPA due to a defect in the synthesis or recycling of the cofactor BH4 (two patients) were excluded. c.441+5G>T was found on 17 alleles. PubMed:23514811

PP3

Broken WT Donor Site predicted in HSF (WT site broken, -14.79) and MaxEnt (-166.44)

PM2

Extremely low frequency in ExAC, 1000G, ESP, and gnomAD (0.00002886)

PM3_Strong

IVS4+5G>T seen in trans with IVS10-11g>a and p.V388M known pathogenic variants in 7 unrelated patients. Upgraded per ClinGen SVI workgroup. PMID: 23514811

IVS4 + 5g>t was seen in 7 patients. Twice in trans with IVS10-11g>a (VarID 607, Pathogenic) in unrelated patients with mild PKU. 5 times in trans with p.V388M (VarID 619, Pathogenic) in 1 patient with classic PKU and 4 patients with mild PKU, all unrelated. PubMed:23514811

PM5

intronic

Approved on: 2018-05-24

Published on: 2019-04-05

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