ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.227A>G (p.Glu76Gly) (rs62507347)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672628 SCV000797752 likely pathogenic Phenylketonuria 2018-02-08 criteria provided, single submitter clinical testing
Invitae RCV000672628 SCV000835094 pathogenic Phenylketonuria 2019-06-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 76 of the PAH protein (p.Glu76Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with PKU (Invitae). In addition, this variant has been reported in combination with another PAH variant in individuals affected with hyperphenylalaninemia or mild hyperphenylalaninemia (PMID: 12655546, 24401910, 11935335). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 639). Experimental studies have shown that this missense change has mild impact on enzyme activity and protein stability (PMID: 17935162, 21953985). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088878 SCV000855423 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing
OMIM RCV000000671 SCV000020821 pathogenic Hyperphenylalaninemia, non-pku 2002-03-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088878 SCV000119475 not provided not provided no assertion provided not provided

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