Evidence Repository - Clinical Genome Resources

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

CA6748955

556894 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d6f8038a-df03-4eef-8fd3-5120ad199adb

Approved on: 2020-04-05

Published on: 2020-04-06

HGVS expressions

NM_000277.2:c.441+1G>C

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

NC_000012.12:g.102877461C>G

CM000674.2:g.102877461C>G

NC_000012.11:g.103271239C>G

CM000674.1:g.103271239C>G

NC_000012.10:g.101795369C>G

NG_008690.1:g.45142G>C

NG_008690.2:g.85950G>C

NM_000277.1:c.441+1G>C

NM_001354304.1:c.441+1G>C

NM_000277.3:c.441+1G>C

NM_001354304.2:c.441+1G>C

ENST00000307000.7:c.426+1G>C

ENST00000549111.5:n.537+1G>C

ENST00000550978.6:n.426G>C

ENST00000551988.5:n.530+1G>C

ENST00000553106.5:c.441+1G>C

Pathogenic

PM2 PM3_Supporting PVS1 PP4_Moderate

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID: 24048906) (PM3_Supporting). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate

PM2

It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2).

PM3_Supporting

It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID: 24048906) (PM3_Supporting). For patients carrying the novel nucleotide lesions, parental DNA samples were sequenced to confirm Mendelian inheritance and cis or trans configurations between IVS4 + 1G > C.

PVS1

The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1).

PP4_Moderate

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