ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.194T>C (p.Ile65Thr) (rs75193786)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000668 SCV000852169 pathogenic Phenylketonuria 2018-04-21 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM3_VeryStrong: Detected with Y414C (P), R408W (P), P281L (P), IVS10nt-11 (P), R252W (P/LP), and R243Q(P). (PMID:12501224; PMID:1301201; PMID:10767174); PP3: Predicted dleterious in SIZFT, Polyphen2, MutationTaster. REVEL=0.985; PP4_Moderate: Detected in a patient with mild PKU. BH4 deficiency excluded. Upgraded per ClinGen PAH EP. (PMID:12501224); PS3: 25% mutant enzyme activity in COS cells as compared in wt (PMID:1301201). 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: (PM3_VeryStrong, PP3, PP4_Moderate, PS3).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078516 SCV000110372 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV000078516 SCV000239044 pathogenic not provided 2020-09-22 criteria provided, single submitter clinical testing Common pathogenic PAH variant most often reported in association with mild-moderate phenylketonuria (PKU) (Pey et al., 2007; Zurfluh et al, 2008; Danecka et al. 2015). It has also been identified in an individual with classic PKU (Couce et al., 2013).; Functional studies demonstrate I65T is associated with reduced phenylalanine hydroxylase activity compared to wild-type (Danecka et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1301187, 17924342, 1301201, 22975760, 30963030, 23500595, 17935162, 11326337, 23559577, 12655546, 25596310, 19036622, 11461190, 21953985, 27121329, 28645531, 25087612, 27264808, 26803807, 19194782, 29030855, 30648773, 30747360, 31980526, 30275481, 31589614, 32668217, 32853555)
Fulgent Genetics,Fulgent Genetics RCV000000668 SCV000611232 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000668 SCV000629186 pathogenic Phenylketonuria 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 65 of the PAH protein (p.Ile65Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs75193786, ExAC 0.03%). This variant has been reported as homozygous or in combination with another PAH variant in multiple individuals affected with PAH-related conditions (PMID: 12655546, 23500595, 25596310). ClinVar contains an entry for this variant (Variation ID: 636). Experimental studies have shown that this missense change causes protein instability and partial PAH enzyme deficiency in vitro (PMID: 12655546, 26803807,17935162). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000668 SCV000696441 pathogenic Phenylketonuria 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The PAH c.194T>C (p.Ile65Thr) variant located in the ACT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22/121240 (1/5509), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected individuals, predominantly as compound heterozygous and was indicated to cause a mild PKU phenotype. In addition, multiple clinical diagnostic laboratories and databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Mayo Clinic Laboratories, Mayo Clinic RCV000000668 SCV000782446 pathogenic Phenylketonuria 2016-05-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078516 SCV000888345 pathogenic not provided 2015-11-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV000000668 SCV001163353 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000668 SCV001193817 likely pathogenic Phenylketonuria 2019-12-24 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.194T>C(I65T) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with classic, variant, or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 11524738, 23500595, 11326337, 1301187, 17935162, 15557004, 8533759, and 9781015. Classification of NM_000277.1(PAH):c.194T>C(I65T) is based on the following criteria: This variant 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.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000668 SCV001251472 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.194T>C (p.I65T) missense variant has been found in the homozygous and compound heterozygous state in individuals with a range of clinical phenotypes including hyperphenylalaninemia; mild phenylketonuria, and classic phenylketonuria (PMID: 9254847; 1301201; 10767174; 12501224).
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000078516 SCV001468123 pathogenic not provided 2020-10-05 criteria provided, single submitter clinical testing
OMIM RCV000000668 SCV000020818 pathogenic Phenylketonuria 1992-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078516 SCV000119461 not provided not provided no assertion provided not provided
GeneReviews RCV000000668 SCV000324886 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000000668 SCV000536896 pathogenic Phenylketonuria 2016-07-19 no assertion criteria provided research
Natera, Inc. RCV000000668 SCV001459226 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000078516 SCV001742867 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000078516 SCV001929157 pathogenic not provided no assertion criteria provided clinical testing

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