ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.829T>G (p.Tyr277Asp) (rs78655458)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000634 SCV000852097 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). Computational prediction tools and conservation analysis suggest that the c.829T>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, PS3
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078531 SCV000110387 pathogenic not provided 2014-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000078531 SCV000239075 pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The Y277D missense variant has been reported as pathogenic variant in the PAH Consortium database.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078531 SCV000601718 pathogenic not provided 2016-10-05 criteria provided, single submitter clinical testing
Invitae RCV000000634 SCV000834704 pathogenic Phenylketonuria 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 277 of the PAH protein (p.Tyr277Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs78655458, ExAC 0.001%). This variant has been reported as homozygous or combination with another pathogenic PAH variant in individuals affected with hyperphenylalaninemia (PMID: 12655546, 2035532, 23500595, 12173030, 8268925, 8632937, 26666653). This variant is also known as c.754C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 603). Experimental studies have shown that this missense change results in a PAH protein with no detectable enzyme activity (PMID: 12655546). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000634 SCV000893942 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000634 SCV000919910 pathogenic Phenylketonuria 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The PAH c.829T>G (p.Tyr277Asp) variant involves the alteration of a conserved nucleotide located in the Aromatic amino acid hydroxylase, C-terminal domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121400 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000000634 SCV000020784 pathogenic Phenylketonuria 1991-06-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078531 SCV000119728 not provided not provided no assertion provided not provided
Counsyl RCV000000634 SCV001132267 pathogenic Phenylketonuria 2018-11-06 no assertion criteria provided clinical testing

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