ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.143T>C (p.Leu48Ser) (rs5030841)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000639 SCV001146709 pathogenic Phenylketonuria 2019-04-08 reviewed by expert panel curation The c.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID: 17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID: 26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID: 23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078511 SCV000110367 pathogenic not provided 2012-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000078511 SCV000239058 pathogenic not provided 2017-03-30 criteria provided, single submitter clinical testing The L48S variant in the PAH gene has been reported as a pathogenicvariant in the PAH Consortium Database. Functional analysis of the L48S variant found that it isassociated with significantly reduced enzyme activity compared to wildtype (Danecka et al., 2015).Individuals homozygous for the L48S variant have been reported with a range of clinical phenotypes,from classic PKU to mild hyperphenylalaninemia (HPA) (Danecka et al., 2015; Shen et al., 2016).Responsiveness to BH4 therapy in individuals harboring the L48S variant has also been inconsistent(Zurfluh et al., 2008; Shen et al., 2016). We interpret L48S as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078511 SCV000280706 pathogenic not provided 2015-04-29 criteria provided, single submitter clinical testing
Invitae RCV000000639 SCV000629185 pathogenic Phenylketonuria 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 48 of the PAH protein (p.Leu48Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs5030841, ExAC 0.01%). This variant has been reported in multiple individuals affected with classical and variant phenylketonuria (PKU) both in the homozygous and in the compound heterozygote state, and it is a well recognized PKU variant in Europe (PMID: 9399896, 1679030, 23430547, 23500595, 23430547). ClinVar contains an entry for this variant (Variation ID: 608). Experimental studies have shown that this missense change causes low PAH enzymatic activity (PMID: 11461190, 25596310, 23500595). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000639 SCV000696437 pathogenic Phenylketonuria 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The PAH c.143T>C (p.Leu48Ser) variant located in the ACT domain (via InterPro) causes a missense change involving a conserved nucleotide, to which 5/5 in silico tools predict a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 10/121396 (1/12135), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous and had been implicated to cause a mild PKU phenotype. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Fulgent Genetics,Fulgent Genetics RCV000000639 SCV000893956 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000000639 SCV000966191 pathogenic Phenylketonuria 2018-10-17 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000639 SCV001193836 pathogenic Phenylketonuria 2019-12-09 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.143T>C(L48S) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with classic or variant PKU. Sources cited for classification include the following: PMID 16879198, 22513348, 12501224, 9521426, 8889590, 23500595, 23430547, 21953985, 17935162 and 1679030. Classification of NM_000277.1(PAH):c.143T>C(L48S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078511 SCV001250401 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
OMIM RCV000000639 SCV000020789 pathogenic Phenylketonuria 2006-08-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078511 SCV000119432 not provided not provided no assertion provided not provided
Myriad Women's Health, Inc. RCV000000639 SCV000677977 pathogenic Phenylketonuria 2015-10-28 no assertion criteria provided clinical testing

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