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.1056del (p.Glu353fs)

CA229312

102499 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 24875ecb-5680-477d-a9a2-ea4bc86ee93f

HGVS expressions

NM_000277.3:c.1056del

NM_000277.3(PAH):c.1056del (p.Glu353fs)

NC_000012.12:g.102844345del

CM000674.2:g.102844345del

NC_000012.11:g.103238123del

CM000674.1:g.103238123del

NC_000012.10:g.101762253del

NG_008690.1:g.78258del

NG_008690.2:g.119066del

ENST00000553106.6:c.1056del

ENST00000307000.7:c.1041del

ENST00000549247.6:n.815del

ENST00000551114.2:n.718del

ENST00000553106.5:c.1056del

ENST00000635477.1:n.160del

ENST00000635528.1:n.571del

NM_000277.1:c.1056del

NM_000277.2:c.1056del

NM_001354304.1:c.1056del

NM_001354304.2:c.1056del

Pathogenic

PM2 PP4_Moderate PVS1_Strong PM3_Very Strong

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1056del (p.Glu353AsnfsTer47) frameshift variant in PAH is predicted to terminate at codon 400 in exon 12, and would not undergo nonsense mediated-decay. This variant was reported in 4 patients within a Spanish cohort with mild and classic PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). The variant was identified in trans with 4 pathogenic variants: p.Ala403Val, p.Ile306Val, c.1066-11G>A and p.Glu280Lys (PMID 27121329). This variant is absent from gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PM3 very strong, and PP4 moderate.

PM2

Absent from gnomAD.

PP4_Moderate

Reported in 4 patients within a Spanish cohort with mild to classic PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329).

PVS1_Strong

Frameshift variant not predicted to undergo NMD, as Ter codon is predicted at aa 400 in last 50bp of preliminary exon (exon 12).

PM3_Very Strong

Detected in trans with 4 pathogenic variants (p. Ala403Val, p.Ile306Val, c.1066-11G>A; and p.Glu280Lys (PMID 27121329)).

Approved on: 2022-06-12

Published on: 2022-06-12

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