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_000277.2(PAH):c.441+1G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229545

102671 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2018-12-22

Published on: 2019-04-06

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

PVS1 PS3_Supporting PP4 PM3 PM2

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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).

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).

PS3_Supporting

The variant has been previously shown by RT-PCR analysis to alter RNA splicing (PMID: 8535445)

The variant has been previously shown by RT-PCR analysis to alter RNA splicing (PMID: 8535445). PubMed:8535445

PP4

Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded.

1 case with classic PKU, found in trans with R408W allele PubMed:22112818

Recurrent mutation among Chinese cases with classic PKU. PubMed:26503515

Chinese founder mutation, classic PKU PubMed:1998345

PM3

1 case with classic PKU, found in trans with R408W allele PubMed:22112818

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.

Curation History

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