ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.121C>T (p.Leu41Phe)

dbSNP: rs62642928
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000697659 SCV001370879 pathogenic Phenylketonuria 2020-06-01 reviewed by expert panel curation The c.121C>T (p.Leu41Phe) variant in PAH has been reported in 2 individuals with mild PKU (BH4 deficiency excluded). (PMID: 21147011, 8268925). This variant is absent in population databases. This variant has 10% enzyme activity PMID: 21953985. This variant was detected with IVS10-11G>A (PMID: 21147011) and R261Q (PMID: 8268925)). Computational prediction tools are conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3.
Invitae RCV000697659 SCV000826284 pathogenic Phenylketonuria 2023-04-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu41 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 8830172, 10679941), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects PAH function (PMID: 11708866). 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102569). This missense change has been observed in individual(s) with mild phenylketonuria and PAH-related disease (PMID: 8268925, 8830172, 9399896, 26503515, 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the PAH protein (p.Leu41Phe).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088803 SCV000119392 not provided not provided no assertion provided not provided

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