ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1199+1G>C (rs62509015)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169248 SCV000852176 pathogenic Phenylketonuria 2018-08-27 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1).
Counsyl RCV000169248 SCV000220530 likely pathogenic Phenylketonuria 2014-07-19 criteria provided, single submitter literature only
GeneDx RCV000088791 SCV000239091 pathogenic not provided 2015-09-03 criteria provided, single submitter clinical testing The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys the canonical splice donor site in intron 11, and is expected to cause abnormal gene splicing. The variant is found in PAH panel(s).
Invitae RCV000169248 SCV000629177 pathogenic Phenylketonuria 2018-09-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with phenylketonuria (PMID: 20187763, 22526846, 22763404, 23856132, 24301756, 26351554, 26413448). It is also known as IVS11+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 102557). 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). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169248 SCV001163713 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169248 SCV001362290 pathogenic Phenylketonuria 2019-02-28 criteria provided, single submitter clinical testing Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246046 control chromosomes (gnomAD) and as been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Zare-Karizi_2011, Dobrowolski_2011, Jeannesson-Thivisol_2015, Liu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dobrowolski_2011), however, does not allow convincing conclusions about the variant effect. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088791 SCV000119378 not provided not provided no assertion provided not provided
Natera, Inc. RCV000169248 SCV001463115 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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