ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.912+1G>A (rs62514956)

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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 RCV000150083 SCV000852153 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00006.; PVS1: Canonical +1 splice site; PP4: Detected in 5 patients with classical PKU. (PMID:8659548). 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, PVS1, PP4).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078537 SCV000110393 pathogenic not provided 2017-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000078537 SCV000617699 pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing The c.912+1 G>A splice site variant in the PAH gene has been previously reported in association with phenylalanine hydroxylase deficiency (Guldberg et al., 1996; Quirk et al., 2012). Individuals homozygous for the c.912+1 G>A variant are reported to have a classic phenylketonuria (PKU) phenotype and this variant is not associated with responsiveness to tetrahydrobiopterin (BH4) therapy (Guldberg et al., 1996; Sarkissian et al., 2012). This pathogenic variant destroys the canonical splice donor site in intron 8, and is expected to cause abnormal gene splicing.
Integrated Genetics/Laboratory Corporation of America RCV000150083 SCV000696471 pathogenic Phenylketonuria 2016-01-21 criteria provided, single submitter clinical testing Variant summary: This c.912+1G>A variant affects a conserved nucleotide in the canonical splice donor site at intron 8. Thus it is predicted to affect normal splicing (such as exon skipping), resulting in loss of function. Loss-of-function due to mutations in this gene is an established disease mechanism in Phenylketoneuria. 5/5 in silico programs via Alamut predict that this variant abrogates the splice donor site. This variant was found in 4/121156 control chromosomes (including broad and large populations from ExAC) at a frequency of 0.000033, which does not exceed the maximal expected frequency of a pathogenic allele (0.0079057) in this gene. This variant has been reported in several PKU patients, including patients with concordant recessive genotypes. One clinical lab and reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
Invitae RCV000150083 SCV000939654 pathogenic Phenylketonuria 2019-11-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 (rs62514956, ExAC 0.006%). Disruption of this splice site has been observed in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 17502162, 26666653). ClinVar contains an entry for this variant (Variation ID: 92752). 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. 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 RCV000150083 SCV001163716 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078537 SCV000119767 not provided not provided no assertion provided not provided
Counsyl RCV000150083 SCV001132444 likely pathogenic Phenylketonuria 2014-01-02 no assertion criteria provided clinical testing

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