ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.441+1G>A (rs62517166)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169579 SCV001572866 pathogenic Phenylketonuria 2018-12-22 reviewed by expert panel curation The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID: 8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID: 22112818) (PM3).
Counsyl RCV000169579 SCV000221082 likely pathogenic Phenylketonuria 2015-01-26 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000088919 SCV000230055 pathogenic not provided 2014-11-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2020-09-08 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088919 SCV000119517 not provided not provided no assertion provided not provided
Natera, Inc. RCV000169579 SCV001455108 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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