ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.60+5G>T (rs62514895)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089000 SCV000224180 pathogenic not provided 2014-11-06 criteria provided, single submitter clinical testing
GeneDx RCV000089000 SCV000239043 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing The c.60+5 G>T variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. Patients who are homozygous for c.60+5 G>T or who are compound heterozygous for c.60+5 G>T and a severe PAH mutation are reported as having classic phenylketonuria (PKU) (BIOPKU Database). The responsiveness of the c.60+5 G>T variant to tetrahydrobiopterin therapy is not clear (Zurfluh et al., 2008).
Invitae RCV000173096 SCV000629202 pathogenic Phenylketonuria 2019-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62514895, ExAC 0.02%). This variant has been reported as homozygous or co-occuring with a second PAH variant in multiple individuals affected with PKU or HPA (PMID: 24941924, 24368688, Invitae). It has been observed as a prevalent PAH mutation in a small group of individuals in Mexico including one homozygous individual affected with classic PKU (PMID: 24941924). ClinVar contains an entry for this variant (Variation ID: 102751). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624585 SCV000741698 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089000 SCV000888351 pathogenic not provided 2018-03-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000173096 SCV001361330 pathogenic Phenylketonuria 2019-12-13 criteria provided, single submitter clinical testing Variant summary: PAH c.60+5G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 251412 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (7.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.60+5G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Sarkissian_2011, Bueno_2013). These data indicate that the variant is very likely to be associated with disease. PAH activity in vitro was null according to PAHdb (http://www.pahdb.mcgill.ca) via Bueno_2013. Four ClinVar submitters (evaluation after 2014) cite 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 RCV000089000 SCV000119604 not provided not provided no assertion provided not provided
Counsyl RCV000173096 SCV000790051 pathogenic Phenylketonuria 2017-03-14 no assertion criteria provided clinical testing

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