ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.932T>C (p.Leu311Pro) (rs62642936)

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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 RCV000000608 SCV001370846 pathogenic Phenylketonuria 2020-02-22 reviewed by expert panel curation The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3.
Counsyl RCV000000608 SCV000220931 likely pathogenic Phenylketonuria 2014-12-02 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000608 SCV001339028 pathogenic Phenylketonuria 2020-03-13 criteria provided, single submitter clinical testing Variant summary: PAH c.932T>C (p.Leu311Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). c.932T>C has been reported in the literature in multiple individuals in affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Rivera_2000, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least two in vitro studies report this variant has an impact on protein function and results in <10% of normal PAH activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000000608 SCV001583222 pathogenic Phenylketonuria 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 311 of the PAH protein (p.Leu311Pro). The leucine residue is highly conserved and there is a moderately physicochemical difference between leucine and proline. This variant is present in population databases (rs62642936, ExAC 0.001%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 9359039, 21871829, 2840952, 9634518, 10394930). ClinVar contains an entry for this variant (Variation ID: 578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. Experimental studies have shown that this variant affects PAH protein function (PMID: 12655546, 17935162, 30037505). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000608 SCV000020758 pathogenic Phenylketonuria 1988-04-19 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089164 SCV000119779 not provided not provided no assertion provided not provided

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