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_000277.3(PAH):c.441+3G>C

CA229546

102672 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 26a2259b-e2bc-4703-badd-78819c8dc4eb

Approved on: 2019-10-18

Published on: 2019-10-18

HGVS expressions

NM_000277.3:c.441+3G>C

NM_000277.3(PAH):c.441+3G>C

NC_000012.12:g.102877459C>G

CM000674.2:g.102877459C>G

NC_000012.11:g.103271237C>G

CM000674.1:g.103271237C>G

NC_000012.10:g.101795367C>G

NG_008690.1:g.45144G>C

NG_008690.2:g.85952G>C

NM_000277.1:c.441+3G>C

NM_000277.2:c.441+3G>C

NM_001354304.1:c.441+3G>C

ENST00000307000.7:c.426+3G>C

ENST00000549111.5:n.537+3G>C

ENST00000550978.6:n.428G>C

ENST00000551988.5:n.530+3G>C

ENST00000553106.5:c.441+3G>C

Pathogenic

PM2 PM3_Very Strong PP4_Moderate

PP3

Evidence Links 6

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.441+3G>C (IVS4+3G>C) variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID: 30050108). This variant was documented 12 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 16256386, 23932990). This variant is absent from the population databases ExAC and gnomAD. 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.

PM2

Absent from population databases gnomAD and ExAC.

PM3_Very Strong

This variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID: 30050108)

This variant was documented in one Chinese patient with mild PKU, with the pathogenic c.721C>T (p.R241C) variant in trans (PMID: 14321076). Parental analysis was performed to confirm compound heterozygosity. PubMed:25894915

This variant was documented in one patient with classic PKU, with the likely pathogenic p.Ala434Asp variant in trans. This variant was documented in one patient with mild PKU, with the VUS Leu444Phe in trans. This variant was documented in one patient with PAH deficiency, with the IVS4-2A>G variant in trans. This variant was documented in one patient with mild hyperphenylalaninemia (MHP), the variant in trans was not specified. This variant was documented in one patient with mild PKU, with the pathogenic p.Arg400Thr variant in trans. Parental analysis was performed to confirm compound heterozygosity. PubMed:28982351

This variant was documented in two patients homozygous for this c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU. This variant was documented in 2 patients with classic PKU, with the pathogenic c.442-1G>A variant in trans. This variant was documented in 1 patient with classic PKU with the p.EX6-96A>G variant in trans. This variant was documented in 1 patient with mild PKU and 1 patient with classic PKU, both with the pathogenic p.Arg243Gln variant in trans. This variant was documented in 1 patient with mild PKU, with the pathogenic p.Arg241Cys variant in trans. This variant was documented in 1 patient with mild PKU with the pathogenic p.Arg408Gln variant in trans. Validation tests on parents were performed using Sanger sequencing. PubMed:30050108

PP4_Moderate

This variant was documented 12 times in patients with PAH deficiency (PMID: 26503515, 16256386, 23932990).

This variant was documented in 1 Chinese patient with classic PKU and 1 patient with moderate PKU (PMID: 23932990). PubMed:23932990

This variant was documented twice in Chinese patients with PKU (PMID: 16256386). PubMed:16256386

This variant was documented seven times in Northern Chinese patients and once in a Southern Chinese patient with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay. PubMed:26503515

PP3

According to in silico splicing predictions, alteration probably damaging (TraP score 0.933). MaxEnt (-103.05% variation) supports that this alteration of the WT acceptor site most probably affects splicing. HSF (-8.61% variation) does not meet the threshold below -10% to consider this a mutation which breaks the splice site.

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