ClinVar Miner

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

dbSNP: rs794727086
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000174462 SCV001146707 likely pathogenic Phenylketonuria 2023-07-23 reviewed by expert panel curation 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.
Eurofins Ntd Llc (ga) RCV000724595 SCV000225769 pathogenic not provided 2015-02-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000174462 SCV000833773 pathogenic Phenylketonuria 2024-10-04 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the PAH mRNA. It is expected to extend the length of the PAH protein by 33 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with PAH-related conditions (PMID: 10679941; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000174462 SCV004201359 likely pathogenic Phenylketonuria 2024-02-10 criteria provided, single submitter clinical testing

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