ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1169A>G (p.Glu390Gly) (rs5030856)

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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 RCV000000657 SCV000852141 pathogenic Phenylketonuria 2018-10-01 reviewed by expert panel curation The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078503 SCV000110359 pathogenic not provided 2013-09-27 criteria provided, single submitter clinical testing
GeneDx RCV000078503 SCV000239089 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing The E390G variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium Database. In vitro studies predict that the E390G missense change is a mild variant associated with residual PAH enzyme activity and results in a mild hyperphenylalaninemia (HPA) phenotype (Trunzo et al., 2013; Pey et al., 2007). E390G is classified as being a tetrahydrobiopterin (BH4) responsive variant (Zurfluh et al., 2008).
Counsyl RCV000000657 SCV000485344 likely pathogenic Phenylketonuria 2016-01-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000656 SCV000696428 pathogenic Hyperphenylalaninemia, non-pku 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The PAH c.1169A>G (p.Glu390Gly) variant involves the alteration of a conserved nucleotide, present in catalytic domain of the protein (Couce_2013) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 12/121202 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000000657 SCV000754075 pathogenic Phenylketonuria 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 390 of the PAH protein (p.Glu390Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs5030856, ExAC 0.02%). This variant has been reported as homozygous or in combination with another PAH variant in several individuals affected with mild hyperphenylalaninemia and mild phenylketonuria (PMID: 8088845, 10472529, 10479481, 12655552, 17935162, 21147011, 21871829, 25596310, 26803807). ClinVar contains an entry for this variant (Variation ID: 625). Experimental studies have shown that this missense change leads to a reduction of 28-46% in the PAH enzymatic activity in vitro (PMID: 17935162 , 22300847, 26803807). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000657 SCV000893266 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000657 SCV000914554 pathogenic Phenylketonuria 2018-08-14 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.1169A>G (p.Glu390Gly) missense variant has been identified in a compound heterozygous state in three individuals with phenylalanine hydroxylase deficiency and in one child with non-PKU hyperphenylalaninemia identified by newborn screening and in three individuals with mild hyperhpenylalaninemila. The variant was also identified in 23/630 alleles of individuals with BH4-responsive mild hyperhpenylalaninemila (Guldberg et al. 1994; Zurflüh et al. 2008; Couce et al. 2013; Trunzo et al. 2013). The p.Glu390Gly variant was absent from 110 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Genome Aggregation Database. Averaged across different cell systems, the p.Glu390Gly variant showed 72.7% residual enzyme activity (Zurflüh et al. 2008), while expression in COS-7 cells revealed that the p.[Glu390Gly];[Arg408Trp] genotype, a recurrent genotype in European and Middle Eastern populations, showed 8.3% residual activity compared to wild type (Danecka et al. 2015). Based on the collective evidence, the p.Glu390Gly variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078503 SCV001247322 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195999 SCV001366426 pathogenic Motor delay; Pes planus; Delayed speech and language development; Hypomimic face; Generalized hypotonia; Joint laxity; Decreased fetal movement; Breech presentation; Slowed slurred speech 2019-08-16 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PS3,PP3. This variant was detected in heterozygous state.
OMIM RCV000000656 SCV000020806 pathogenic Hyperphenylalaninemia, non-pku 1999-08-01 no assertion criteria provided literature only
OMIM RCV000000657 SCV000020807 pathogenic Phenylketonuria 1999-08-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078503 SCV000119363 not provided not provided no assertion provided not provided

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