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.1315+4A>G

CA229430

102589 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3b5d1254-5e2c-4369-9776-c9b89cef8ab7

Approved on: 2019-11-05

Published on: 2019-11-06

HGVS expressions

NM_000277.3:c.1315+4A>G

NM_000277.3(PAH):c.1315+4A>G

NC_000012.12:g.102840396T>C

CM000674.2:g.102840396T>C

NC_000012.11:g.103234174T>C

CM000674.1:g.103234174T>C

NC_000012.10:g.101758304T>C

NG_008690.1:g.82207A>G

NG_008690.2:g.123015A>G

NM_000277.1:c.1315+4A>G

NM_000277.2:c.1315+4A>G

NM_001354304.1:c.1315+4A>G

ENST00000307000.7:c.1300+4A>G

ENST00000551114.2:n.977+4A>G

ENST00000553106.5:c.1315+4A>G

ENST00000635477.1:n.419+4A>G

ENST00000635528.1:n.830+4A>G

Likely Pathogenic

PM2 PM3_Strong PP4_Moderate PP3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1315+4A>G variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in four patients diagnosed with PAH deficiency (PMID: 16256386, 28982351, 25456745, 23932990). This variant is present in the population database gnomAD at a frequency below 0.0002. According to in silico splicing predictions, this alteration is probably damaging (TraP score 0.992). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3.

PM2

Absent from population database ExAC. Present in East Asian populations at a frequency of 0.00005 (gnomAD).

PM3_Strong

This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in 4 patients diagnosed with PKU or Hyperphenylalaninemia (PMID: 16256386, 28982351, 25456745, 23932990).

This variant was documented in 1 PKU patient with the pathogenic c.1197A>T (p.V399V) variant in trans. This study included 655 PKU patients and phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through urinary pterin analysis. Parental analysis was performed to confirm compound heterozygosity. PubMed:28982351

This variant was documented in 1 Northern Chinese patient diagnosed with Classical PKU (Phe ≥ 1200 µmol/L) through neonatal screening. The variant in trans was the likely pathogenic R241fsX5 (c.722delG) variant. This study included 185 unrelated Northern Chinese PKU patients. It was not specified whether parental analysis was performed to confirm compound heterozygosity. PubMed:16256386

This variant was documented in 1 patient with HPA and the likely pathogenic c.724C>T variant in trans. It was not specified whether parental analysis was performed to confirm compound heterozygosity. PubMed:25456745

This variant was documented in 1 patient with classic PKU with the pathogenic R243Q variant in trans. It was not specified whether parental analysis was performed to confirm compound heterozygosity. PubMed:23932990

PP4_Moderate

This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515).

This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). It was not specified whether the 2 alleles in Southern China were from 2 compound heterozygous individuals or from one homozygous individual. This study included 796 PKU patients from mainland China diagnosed through neonatal screening 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 0.992). HSF (-42.16%) and MaxEnt (-40.25%) agree that this alteration of the WT acceptor site most probably affects splicing.

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