ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.913-7A>G (rs62517165)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000589029 SCV001370819 likely pathogenic Phenylketonuria 2020-02-16 reviewed by expert panel curation The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589029 SCV000696472 pathogenic Phenylketonuria 2016-04-18 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, the variant was classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000089156 SCV000703341 pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000589029 SCV000893938 likely pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089156 SCV001470580 pathogenic not provided 2019-11-12 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low nucleotide conservation. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV000589029 SCV001580108 pathogenic Phenylketonuria 2020-07-23 criteria provided, single submitter clinical testing This sequence change falls in intron 8 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 individuals with phenylketonuria (PKU) (PMID: 29653233, 29499199, 26600521). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 102894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089156 SCV000119770 not provided not provided no assertion provided not provided
Counsyl RCV000589029 SCV000791679 likely pathogenic Phenylketonuria 2017-05-19 no assertion criteria provided clinical testing
Natera, Inc. RCV000589029 SCV001463132 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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