ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.533A>G (p.Glu178Gly) (rs77958223)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000150087 SCV000852155 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. ExAC MAF=0.00017; PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841; PS3: 39% residual phenylalanine hydroxylase activity (PMID:17935162); PP4_Moderate: Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP. (PMID:18294361; PMID:9634518); PM3_Strong: In trans with 3 pathogenic variants (PMID:18294361). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078526 SCV000110382 pathogenic not provided 2017-05-17 criteria provided, single submitter clinical testing
Invitae RCV000150087 SCV000629201 pathogenic Phenylketonuria 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 178 of the PAH protein (p.Glu178Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs77958223, ExAC 0.02%). This variant has been reported to co-occur with another PAH variant in multiple individuals affected with hyperphenylalaninemia and phenylketonuria (PMID: 7707686, 10479481, 8632937, 18299955, 16198137, 22330942, 23357515, 22513348, 19948162). ClinVar contains an entry for this variant (Variation ID: 92746), Experimental studies have shown that this missense change causes a reduction of PAH enzyme activity (PMID: 10479481, 26803807). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000150087 SCV000893949 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000150087 SCV000917920 pathogenic Phenylketonuria 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The PAH c.533A>G (p.Glu178Gly) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. In vitro functional studies reported that the variant protein has a 2040% residual activity when in hemizygous/homozygous form (Benit 1999, Shen 2016), however when it was co-expressed e.g. with the variant Q232E (that had 41% activity in homozygous form), the overall phenylalanine hydroxylase activity was 55%, demonstrating a positive interallelic complementation effect (Shen 2016). This variant was found in 22/276946 control chromosomes at a frequency of 0.0000794, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in the literature with a range of phenotypes depending on the genetic background, i.e. several individuals presenting with mild hyperphenylalaninemia were described (Benit 1999, Rivera 2011, Reblova 2013, Aldamiz-Echevarria 2016), but the variant was also found in numerous patients with mild, moderate or classic PKU phenotype (Bercovich 2008, Reblova 2013). At least two studies reported the variant of interest as a tetrahydrobiopterin (BH4)-responsive (Zurfluh 2008, Rivera 2011), suggesting that this variant represent a mild mutation. In general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078526 SCV000119580 not provided not provided no assertion provided not provided
Counsyl RCV000150087 SCV000485351 pathogenic Phenylketonuria 2016-01-22 no assertion criteria provided clinical testing

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