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_000277.2(PAH):c.1357_*2delTAAAG (p.Ter453Profs)

194161 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dd07cd11-a480-4024-b568-1aabf10c6428

Approved on: 2023-07-23

Published on: 2023-07-23

HGVS expressions

NM_000277.2:c.1357_*2delTAAAG

NM_000277.2(PAH):c.1357_*2delTAAAG (p.Ter453Profs)

NM_000277.3(PAH):c.1357_*2del (p.Ter453ProextTer?)

Likely Pathogenic

PM2_Supporting PP4_Moderate PM4 PM3_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.1357_*2delTAAAG (p.Ter453Profs) variant in PAH has been reported in multiple individuals with PAH deficiency; one with other causes of hyperphenylalninemia ruled out with panel sequencing. (PP4_Moderate; PMID: 10679941, data share with Invitae). This variant is at low frequency in population databases (TopMed AF=0.00001). This variant was detected with known pathogenic/likely pathogenic variants: p.L48 (unknown phase, PMID: 10679941); c.1066-11G>A, p.Arg408Trp, p.Arg155Pro, (unknown phase, PMID: 32668217); and Leu348Val (in trans, data share with Invitae). The deletion p.Ter453Profs is predicted to abolish the stop codon and causes an elongation of the polypeptide by 35 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2-supporting, PM3_strong, PM4.

PM2_Supporting

TopMed: delCTTTA=0.00001 (Sample size 125568)

PP4_Moderate

Detected in a Patient with Mild PKU. Cofactor deficiency was excluded by the BH4 test. c.1357-1361del (Ter452del5bp). PMID: 10679941. Detected in patient with Phe 308 umol/L, panel performed: DNAJC12, GCH1, PCBD1, PTS, QDPR, SLC25A13, SPR (Invitae)

PM4

The deletion Ter452del5bp affects the translation termination codon and causes an elongation of the polypeptide by 35 amino acids.

PM3_Strong

Detected with known pathogenic variant p.L48S, "in trans" (PMID: 10679941). c.1066-11G>A (P), p.Arg408Trp (P), and p.Arg155Pro (LP) (unknown phase, PMID: 32668217); Leu348Val in trans (P by 15 submitters); Arg241Leu, unknown phase (P, Invitae). Parental confirmation not reported. 3.25 points

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