ClinVar Miner

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

dbSNP: rs62509015
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000632882 SCV001448301 pathogenic Phenylketonuria 2020-10-15 reviewed by expert panel curation This c.1199+1G>A variant in PAH was reported in 1 Czech patient with PAH deficiency (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF: 0.00001). This variant in the +1 splice donor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV000632882 SCV000754083 pathogenic Phenylketonuria 2022-08-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 102556). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 9634518, 30159852; Invitae). This variant is present in population databases (rs62509015, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Counsyl RCV000632882 SCV000792852 likely pathogenic Phenylketonuria 2017-07-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV000632882 SCV004209630 pathogenic Phenylketonuria 2023-07-26 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088790 SCV000119377 not provided not provided no assertion provided not provided
Natera, Inc. RCV000632882 SCV001463116 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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