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.1065+1G>A

CA229315

102501 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8de0de63-abcc-463d-ad96-ba40efd5b321

HGVS expressions

NM_000277.3:c.1065+1G>A

NM_000277.3(PAH):c.1065+1G>A

NC_000012.12:g.102844335C>T

CM000674.2:g.102844335C>T

NC_000012.11:g.103238113C>T

CM000674.1:g.103238113C>T

NC_000012.10:g.101762243C>T

NG_008690.1:g.78268G>A

NG_008690.2:g.119076G>A

ENST00000307000.7:c.1050+1G>A

ENST00000553106.5:c.1065+1G>A

NM_000277.1:c.1065+1G>A

NM_000277.2:c.1065+1G>A

NM_001354304.1:c.1065+1G>A

NM_001354304.2:c.1065+1G>A

Likely Pathogenic

PM3_Supporting PP4 PVS1_Strong PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH variant c.1065+1G>A (IVS10+1G>A) affects the canonical splice site (donor site). Loss of function in the PAH gene is a known mechanism of disease. Exon skipping is predicted to not disrupt the reading frame. This variant is predicted to alter a region that is critical to protein function. The PAH variant c.1065+1G>A (IVS10+1G>A) was identified in two French patients with mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L) with the likely pathogenic variant c.261C>A (p.Ser87Arg) and with the pathogenic variant c.1169A>G (p.Glu390Gly)(PMID: 26666653). The PAH variant c.1065+1G>A was also reported in an European patient with PAH deficiency (PMID: 10679941). According to gnomAD, the PAH variant c.1065+1G>A (IVS10+1G>A) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Finnish) population (0.00005). In summary, this variant meets the criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4, and PVS1_Strong.

PM3_Supporting

The PAH variant c.1065+1G>A (IVS10+1G>A) was identified in two French patients with mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L) with the PHA likely pathogenic variant c.261C>A (p.Ser87Arg)(ClinVar ID: 583) PM3 Points: 1*0.25=0.25 and with the PAH pathogenic variant c.1169A>G (p.Glu390Gly)(ClinVar ID: 625) PM3 Points: 1*0.5=0.5 (PM3 Points: 0.75_Supporting). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test (PMID: 26666653).

PP4

The PAH variant c.1065+1G>A (IVS10+1G>A) was identified in two French patients with mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test (PMID: 26666653).

PVS1_Strong

The PAH variant c.1065+1G>A (IVS10+1G>A) is a canonical splice site (donor site). Loss of function in the PAH gene is a known mechanism of disease. Nine null variants in exon 10 of the PAH gene have been reported. Exon skipping is not predicted to disrupt the reading frame. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.914). HSF (-30.19% variation) and MaxEnt (-86.47% variation) agree that this alteration of the WT donor site most probably affects splicing. Therefore, PVS1_Strong is applied.

PM2

According to gnomAD, the PAH variant c.1065+1G>A (IVS10+1G>A) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Finnish) population (0.00005). This variant is absent from the ExAC, PAGE, and ESP population databases.

Approved on: 2021-03-21

Published on: 2021-03-21

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