ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.441+5G>T (rs62507321)

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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, RCV000150089 SCV000852117 pathogenic Phenylketonuria 2018-05-24 reviewed by expert panel curation The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong
Counsyl RCV000150089 SCV000791712 pathogenic Phenylketonuria 2017-05-30 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078521 SCV000119521 not provided not provided no assertion provided not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078521 SCV000110377 pathogenic not provided 2014-07-22 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000150089 SCV000611225 likely pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000078521 SCV000239051 pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing The c.441+5 G>T mutation in the PAH gene has been reported as a pathogenic mutation in the PAH Consortium database. In vitro studies predict that c.441+5 G>T is anull variant associated with no residual phenylalanine hydroxylase activity (Bueno et al., 2013). Anindividual homozygous for c.441+5 G>T was reported to have a classic phenylketonuria (PKU)phenotype (Vela-Amieva et al., 2015). However, individuals compound heterozygous for c.441+5 G>Tand a PAH variant known to be associated with a classic PKU phenotype were reported to havemoderate PKU, and an individual compound heterozygous for c.441+5 G>T and a mild PAH variantwas reported to have classic PKU (Bueno et al., 2013). Therefore, reports of the phenotypeassociated with the c.441+5 G>T variant are not consistent. Many individuals with c.441+5 G>T andanother PAH variant were not found to be responsive to tetrahydrobiopterin (BH4), but data are stillunclear (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015).
Integrated Genetics/Laboratory Corporation of America RCV000150089 SCV000696449 pathogenic Phenylketonuria 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The PAH c.441+5G>T variant involves the alteration of a conserved intronic nucleotide with 4/5 splice prediction tools predicting a significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121412 (1/24271), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126 (0.0079057). Multiple publications cite the variant in affected individuals who are homozygous and compound heterozygous, along with multiple databases/clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000150089 SCV000754087 pathogenic Phenylketonuria 2018-01-18 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62507321, ExAC 0.02%). This variant has been reported as homozygous or on the opposite chromosome (in trans) from other pathogenic variants in an several individuals affected with phenylketonuria or hyperphenylalaninemia (PMID: 9429153, 17502162, 23514811, 23764561, 24296287, 24368688, 24941924, 25596310, 26666653). ClinVar contains an entry for this variant (Variation ID: 92742). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

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