Variant: NM_000277.2(PAH):c.441+1G>A

CA229545

102671 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 19dc340b-f7df-4865-bba3-db4b17bddcab

HGVS expressions

NM_000277.2:c.441+1G>A
NM_000277.2(PAH):c.441+1G>A
NM_000277.1:c.441+1G>A
NM_001354304.1:c.441+1G>A
NM_000277.3:c.441+1G>A
NM_001354304.2:c.441+1G>A
ENST00000307000.7:c.426+1G>A
ENST00000549111.5:n.537+1G>A
ENST00000550978.6:n.426G>A
ENST00000551988.5:n.530+1G>A
ENST00000553106.5:c.441+1G>A
NC_000012.12:g.102877461C>T
CM000674.2:g.102877461C>T
NC_000012.11:g.103271239C>T
CM000674.1:g.103271239C>T
NC_000012.10:g.101795369C>T
NG_008690.1:g.45142G>A
NG_008690.2:g.85950G>A

Pathogenic

• Met criteria codes: PVS1 PP4 PM2 PM3 PS3_Supporting

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID: 8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID: 22112818) (PM3).

Met criteria codes

• PVS1: Canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria).
• PP4: Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded.
• PM2: Variant is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002.
• PS3_Supporting: The variant has been previously shown by RT-PCR analysis to alter RNA splicing (PMID: 8535445)

Approved on: 2018-12-22

Published on: 2019-04-06