ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1097C>A (p.Pro366His) (rs62516098)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672118 SCV000797184 likely pathogenic Phenylketonuria 2018-01-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672118 SCV000917924 pathogenic Phenylketonuria 2018-05-21 criteria provided, single submitter clinical testing Variant summary: PAH c.1097C>A (p.Pro366His) results in a non-conservative amino acid change located in the catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121284 control chromosomes. c.1097C>A has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia and mild PKU responsive to BH4. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000672118 SCV001203263 pathogenic Phenylketonuria 2020-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 366 of the PAH protein (p.Pro366His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another PAH variant in several individuals affected with phenylketonuria and hyperphenylalaninemia (PMID: 26210745, 22841515, 17096675, 19609714, 19292873). ClinVar contains an entry for this variant (Variation ID: 102521). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088754 SCV000119338 not provided not provided no assertion provided not provided

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