ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1042C>G (p.Leu348Val) (rs62516092)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078498 SCV000110354 pathogenic not provided 2014-05-20 criteria provided, single submitter clinical testing
GeneDx RCV000078498 SCV000490682 pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing The L348V pathogenic variant in the PAH gene has been reported previously in individuals with both mild and moderate PAH deficiency (Pey et al., 2007), and the residual phenylalanine hydroxylase activity in vitro is reported to be 25-44% (Couce et al., 2013; Zurfluh et al., 2008; Pey et al., 2007). The L348V variant has been associated with tetrahydrobiopterin (BH4) responsiveness (Zurfluh et al., 2008; Dobrowolski et al., 2009). The L348V variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L348V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Missense variants in nearby residues (A345T, A345S, G346R, G346E, L347F, S349P, S349A, S349L, S350T, S350Y) have been reported in the Human Gene Mutation Database in association with phenylalanine hydroxylase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L348V as a pathogenic variant,
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078498 SCV000601705 pathogenic not provided 2017-02-04 criteria provided, single submitter clinical testing
Invitae RCV000150080 SCV000629168 pathogenic Phenylketonuria 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 348 of the PAH protein (p.Leu348Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs62516092, ExAC <0.01%). This variant is a well known mutation that has been reported in individuals affected with classic and mild phenylketonuria (PKU) (PMID: 8632937, 1301187, 18937047, 20082265). ClinVar contains an entry for this variant (Variation ID: 92727). This variant is known to cause partial reduction of PAH enzymatic activity (PMID: 25596310, 10479481, 17935162, 23500595). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000150080 SCV000893268 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000150080 SCV000917927 pathogenic Phenylketonuria 2018-07-24 criteria provided, single submitter clinical testing Variant summary: PAH c.1042C>G (p.Leu348Val) results in a conservative amino acid change located in the in the catalytic domain (Sarkissian 2011) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 276972 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00011 vs 0.0079), allowing no conclusion about variant significance. c.1042C>G has been reported in the literature in multiple individuals affected with the classic and mild form of Phenylalanine Hydroxylase Deficiency (i.e. Phenylketonuria) (e.g. Quirk 2012, Sarkissian 2011, Jeannesson-Thivisol 2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 20%-40% of normal activity (see e.g. Benit 1999, Zurfluh 2008), with variable Bh4 responsivity, depending on the genotype (Sarkissian 2011, Jeannesson-Thivisol 2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078498 SCV001249173 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078498 SCV000119300 not provided not provided no assertion provided not provided
Counsyl RCV000150080 SCV000485384 pathogenic Phenylketonuria 2016-01-22 no assertion criteria provided clinical testing

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