ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1127del (p.Asn376fs)

dbSNP: rs62642921
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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 RCV001857428 SCV004222623 pathogenic Phenylketonuria 2023-10-15 reviewed by expert panel curation The c.1127del (p.Asn376fs) variant in PAH is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a Mexican patient with classic PKU with the pathogenic variant c.1066-11G>A (PMID: 24941924; PP4, PM3_supporting). This variant has an extremely low frequency in gnomAD (MAF=0.00002895). In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PM3_supporting, PP4.
Invitae RCV001857428 SCV002243444 pathogenic Phenylketonuria 2023-04-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn376Ilefs*24) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62642921, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102532). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 24941924).
Baylor Genetics RCV001857428 SCV004209702 pathogenic Phenylketonuria 2023-02-15 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088765 SCV000119349 not provided not provided no assertion provided not provided

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