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_000277.3(PAH):c.969+5G>A

CA229879

102915 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6024bb15-c9cd-49b5-af43-eacea55dd334

HGVS expressions

NM_000277.3:c.969+5G>A

NM_000277.3(PAH):c.969+5G>A

NC_000012.12:g.102846890C>T

CM000674.2:g.102846890C>T

NC_000012.11:g.103240668C>T

CM000674.1:g.103240668C>T

NC_000012.10:g.101764798C>T

NG_008690.1:g.75713G>A

NG_008690.2:g.116521G>A

NM_000277.1:c.969+5G>A

NM_000277.2:c.969+5G>A

NM_001354304.1:c.969+5G>A

ENST00000307000.7:c.954+5G>A

ENST00000549247.6:n.728+5G>A

ENST00000551114.2:n.631+5G>A

ENST00000553106.5:c.969+5G>A

ENST00000635477.1:n.74-2459G>A

ENST00000635528.1:n.484+5G>A

Pathogenic

PM2 PP4_Moderate PM3_Very Strong PP3

Evidence Links 6

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.969+5G>A variant in PAH has been reported in at least 4 individuals with classic PKU (BH4 deficiency excluded) (PP4_moderate; PMID: 24048906). This variant is absent in population databases (PM2). This variant has been detected in the homozygous state and in compound heterozygotes with at least 6 Pathogenic/Likely Pathogenic variants including A300S (ClinVar: 92751, Pathogenic), R176X (ClinVar: 102723, Pathogenic), c.168+5G>C (ClinVar 102606, Pathogenic), and c.913-7A>G (ClinVar: 102894, Likely Pathogenic), c.1066-11G>A (ClinVar: 607, Pathogenic), E280K (ClinVar 580, Pathogenic) (PM3_VeryStrong; PMID: 30159852, PMID:10947211, PMID:24048906, PMID:30389586, PMID:24368688). Computational prediction tools suggest that c.969+5G>A may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP3, PP4_Moderate.

PM2

Variant is absent from all gnomAD and 1000 Genomes populations.

PP4_Moderate

At least four probands have been reported with classic PKU (serum Phe levels >1200uM) and exclusion of BH4 deficiency.

PM3_Very Strong

From PMID: 30159852, 32 Iranian patients genetically diagnosed with PKU were identified with this variant. This includes 23 homozygotes with serum Phe 11-54 mg/dL: patients 73, 140, 142, 166, 237, 314, 341, 370, 390, 405, 422, 435, 446, 558, 563, 574, 582, 589, 591, 600, 601, 612, 613 (1pt). Another 9 compound heterozygous patients with unconfirmed phase were also identified. Two patients with genotype c.1066-11G>A (ClinVar: 607, Pathogenic);c.969+5G>A: patient 53 serum Phe 15 mg/dL and patient 564 serum Phe 5.4 mg/dL (1pt). Patient 562 with genotype c.168+5G>C (ClinVar 102606, Pathogenic);c.969+5G>A abd serum Phe 14.2 mg/dL (0.5pt). Four patients with genotype p.Arg176Ter (ClinVar: 102723, Pathogenic);c.969+5G>A: patient 260 serum Phe 20 mg/dL, patient 106 serum Phe 15 mg/dL, patient 584 serum Phe NA, patient 628 serum Phe 20 mg/dL (1.5pt for 3 patients with Phe levels). Patient 628 with genotype c.969+5G>A;p.L258R (not previously classified) and serum Phe NA, (0pt). And patient 196 with genotype p.E280K (ClinVar 580, Pathogenic);c.969+5G>A and serum Phe 21 mg/dL (0.5pt). This variant has also been identified in trans with variants ClinVar: 102894, Likely Pathogenic) 0.25pt (PMID: 24048906) and Ala300Ser (ClinVar: 92751, Pathogenic) 0.5pt (PMID: 10947211). TOTAL: At least 26 homozygotes plus compound heterozygotes with at least 6 different Likely Pathogenic/Pathogenic variants. 5.5pt

PubMed:30389586

PubMed:24048906

PubMed:10947211

PubMed:26413448

PubMed:20920871

PubMed:24368688

PP3

Human splice finder reports WT donor splice site broken at -14.54%, MaxEnt reports -79.87% variation.

Approved on: 2019-12-22

Published on: 2019-12-22

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