ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.503del (p.Tyr168fs) (rs199475661)

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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 RCV000375882 SCV000852094 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. ExAC MAF: 0.00001.; PP4: Detected in PKU patient in international phase II clinical trial for sapropterin. (PMID:23430918). 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 RCV000088953 SCV000330983 pathogenic not provided 2015-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000375882 SCV000696451 pathogenic Phenylketonuria 2016-12-06 criteria provided, single submitter clinical testing Variant summary: The PAH c.503delA (p.Tyr168Serfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.526C>T, p.Arg176X; c.1089delG, p.Lys363fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121256 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in two unrelated patients who carry c.1222C>T/p.R408W (pathogenic) in trans (Sarkissian_2011 and one internal sample). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088953 SCV000119555 not provided not provided no assertion provided not provided

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