ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1055del (p.Gly352fs) (rs62516094)

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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 RCV000267428 SCV000852166 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). 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: (PVS1, PM2, PP4).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088729 SCV000343399 pathogenic not provided 2016-06-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088729 SCV000601706 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000267428 SCV000696423 pathogenic Phenylketonuria 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The c.1055delG (p.Gly352Valfs) variant in PAH gene is a frameshift change that results in the loss of ~162 amino acids of the PAH protein (~11%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present at a low frequency in the large control population datasets of ExAC (8.351e-06; 1/119744 chrs tested). The c.1055delG has been reported in multiple affected individuals with biochemically confirmed PKU via published reports. This variant is associated with predominantly severe clinical phenotype and homozygous patients are non-responsive to BH4 therapy. Lastly, it is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Counsyl RCV000267428 SCV000789345 pathogenic Phenylketonuria 2017-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000267428 SCV000915568 pathogenic Phenylketonuria 2018-08-14 criteria provided, single submitter clinical testing The PAH c.1055delG (p.Gly352ValfsTer48) variant is predicted to result in a frameshift and premature truncation of the protein. Across a selection of the available literature, the p.Gly352ValfsTer48 variant has been reported in at least 37 unrelated individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in 21 individuals, in a compound heterozygous state in 15 individuals, and in a heterozygous state in one individual in whom a second variant was not identified (Rozen et al. 1994; Daniele et al. 2009; Dahri et al. 2010; Jeannesson-Thivisol et al. 2015). Most of these cases showed a classic phenotype; 14 individuals who were severely affected displayed clinical symptoms due to delayed diagnosis and treatment. Control data are unavailable for the p.Gly352ValfsTer48 variant, which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. Based on the collective evidence, the p.Gly352ValfsTer48 variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088729 SCV000119311 not provided not provided no assertion provided not provided

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