ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1199+17G>A (rs62508613)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088789 SCV000330982 likely pathogenic not provided 2016-04-29 criteria provided, single submitter clinical testing
Unidade de Bioquimica Genetica,Centro Hospitalar do Porto RCV000316500 SCV000616624 likely pathogenic Phenylketonuria 2017-11-10 criteria provided, single submitter clinical testing The variant was observed in four patients, two with a diagnosis of phenylketonuria (PKU) and the other two with a diagnosis of mild hyperphenylalaninemia (MHP). In the two PKU patients, the variant was found in compound heterozygosity with IVS10-11G>A (c.1066-11G>A), in intron 10, and c.250G>T (p.D84Y), in exon 3. Meanwhile, in the two MHP patients, it was found with IVS2+5G>C (c.168+5G>C), in intron 2, and c.754C>T (p.R252W), in exon 7. In silico analysis in Human Splicing Finder showed that it activates an intronic cryptic acceptor site, which potentially alters splicing.
Invitae RCV000316500 SCV000629176 pathogenic Phenylketonuria 2019-11-10 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in individuals affected with phenylketonuria (PKU) (PMID: 11139255, Invitae). This variant is also known as IVS11+17G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102555). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29684050). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000088789 SCV000709881 likely pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing The c.1199+17 G>A variant has previously been reported in the compound heterozygous state in an individual with moderate PKU (Acosta et al., 2000) and in unrelated patients referred for PAH sequencing at GeneDx. The c.1199+17 G>A variant is not observed in large population cohorts (Lek et al., 2016). Although in-silico splice prediction models do not predict that c.1199+17 G>A affects splicing, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000316500 SCV000799396 likely pathogenic Phenylketonuria 2018-04-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000316500 SCV001163712 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088789 SCV000119376 not provided not provided no assertion provided not provided

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