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_000277.3(PAH):c.1315+6T>A

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CA229431

102590 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 73124e93-6e07-43ad-9e9a-4a180d6fbdec

Approved on: 2019-11-05

Published on: 2019-11-06

HGVS expressions

NM_000277.3:c.1315+6T>A

NM_000277.3(PAH):c.1315+6T>A

NC_000012.12:g.102840394A>T

CM000674.2:g.102840394A>T

NC_000012.11:g.103234172A>T

CM000674.1:g.103234172A>T

NC_000012.10:g.101758302A>T

NG_008690.1:g.82209T>A

NG_008690.2:g.123017T>A

NM_000277.1:c.1315+6T>A

NM_000277.2:c.1315+6T>A

NM_001354304.1:c.1315+6T>A

ENST00000307000.7:c.1300+6T>A

ENST00000551114.2:n.977+6T>A

ENST00000553106.5:c.1315+6T>A

ENST00000635477.1:n.419+6T>A

ENST00000635528.1:n.830+6T>A

Pathogenic

PM3_Very Strong PP4_Moderate PM2

PP3

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1315+6T>A (IVS12+6T>A) variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515). This variant was documented in at least 7 patients with PAH deficiency, with a pathogenic PAH variant in trans (PMID: 16256386, 23932990, 28982351). 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: PM2, PP4_moderate, PM3_very strong.

PM3_Very Strong

This variant was documented in at least 7 Chinese patients with PAH deficiency, with a pathogenic or likely pathogenic PAH variant in trans (PMID: 16256386, 23932990).

This variant was documented in a mild PKU patient with the pathogenic p.Arg241His variant in trans. This variant was also documented in a patient with mild PKU with the likely pathogenic p.His107Arg variant in trans. This variant was documented in a mild PKU patient with the likely pathogenic c.722delG variant in trans. This variant was documented in a patient with mild PKU with the pathogenic p.Tyr356* variant in trans. Parental analysis was performed to confirm compound heterozygosity (PMID: 28982351). PubMed:28982351

This variant was documented in 1 Han Chinese patient patient with mild hyperphenylalaninemia (MHP), and the pathogneic R243Q variant in trans; this variant was also documented in a second Han Chinese patient with mild hyperphenylalaninemia (MHP), and the pathogenic R241C variant in trans. Parental analysis was not performed to confirm compound heterozygosity. PubMed:23932990

This variant was documented in one Northern Chinese patient with mild PKU, with the pathogenic PAH variant Arg413Pro in trans (PMID: 16256386). It was not specified whether parental analysis was performed to confirm compound heterozygosity. PubMed:16256386

PP4_Moderate

This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency (PMID: 26503515).

This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients 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

PM2

Absent from population databases gnomAD and ExAC.

PP3

According to in silico splicing predictions, alteration likely benign (TraP score 0.116). HSF (-35.72% variation) and MaxEnt (-37.2% variation) agree that this alteration of the WT donor site most probably affects splicing.

Curation History

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