ClinVar Miner

Submissions for variant NM_000277.2(PAH):c.441+1G>A (rs62517166)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169579 SCV000221082 likely pathogenic Phenylketonuria 2015-01-26 criteria provided, single submitter literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088919 SCV000119517 not provided not provided no assertion provided not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088919 SCV000230055 pathogenic not provided 2014-11-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169579 SCV000696448 pathogenic Phenylketonuria 2016-07-18 criteria provided, single submitter clinical testing Variant summary: The PAH c.441+1G>A variant is located at a conserved intronic position, known to affect splicing, with 5/5 splice prediction tools predicting a significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121412, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000169579 SCV000754085 pathogenic Phenylketonuria 2017-10-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs62517166, ExAC 0.001%). This variant has been reported in combination with other PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria (PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308). This variant is also known as IVS4+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102671). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). A different variant affecting this nucleotide (c.441+1G>C) has been determined to be pathogenic (PMID: 24048906). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Experimental studies have shown that this intronic change causes an aberrant RNA splicing (PMID: 8535445). For these reasons, this variant has been classified as Pathogenic.

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