ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1024del (p.Ala342fs)

dbSNP: rs63581460
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000412182 SCV000852167 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Absent from ExAC, gnomAD, 1000G, ESP; PVS1: Frameshift variant; PP4_Moderate: Reported in patients with PAH deficiency. Bh4 defects excluded. (PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate).
GeneDx RCV000088706 SCV000329861 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The c.1024delG pathogenic variant has been reported previously in association with PKU (Guldberg et al., 1998; Liu et al., 2015). The deletion causes a frameshift starting with codon Alanine 342, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Ala342HisfsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Counsyl RCV000412182 SCV000486461 pathogenic Phenylketonuria 2016-06-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000412182 SCV000917918 pathogenic Phenylketonuria 2023-11-15 criteria provided, single submitter clinical testing Variant summary: PAH c.1024delG (p.Ala342HisfsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251246 control chromosomes. c.1024delG has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldber_1998, Li_2015, Zhu_2013, Liu_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9634518, 26503515, 23932990, 26600521). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000412182 SCV002246006 pathogenic Phenylketonuria 2021-08-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with phenylketonuria (PMID: 26503515, 26600521). This variant is also known as c.1023del (p.A342Hfs*59). ClinVar contains an entry for this variant (Variation ID: 102475). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala342Hisfs*58) 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).
Baylor Genetics RCV000412182 SCV004209672 pathogenic Phenylketonuria 2023-05-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088706 SCV000119286 not provided not provided no assertion provided not provided

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