ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1024del (p.Ala342fs) (rs63581460)

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Total submissions: 5
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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
Integrated Genetics/Laboratory Corporation of America RCV000412182 SCV000917918 pathogenic Phenylketonuria 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The PAH c.1024delG (p.Ala342HisfsX58) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1055delG (p.Gly352fsX48), c.1089delG (p.Lys363fsX37)). The variant was reported in the literature in multiple patients with PKU (Zhu 2013, Liu 2015, Li 2015). This variant is absent in 276966 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088706 SCV000119286 not provided not provided no assertion provided not provided

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