ClinVar Miner

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

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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, 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).
Counsyl RCV000000668 SCV000486009 likely pathogenic Phenylketonuria 2016-03-16 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078516 SCV000119461 not provided not provided no assertion provided not provided
Division of Human Genetics,Children's Hospital of Philadelphia RCV000000668 SCV000536896 pathogenic Phenylketonuria 2016-07-19 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078516 SCV000110372 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000000668 SCV000611232 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000078516 SCV000239044 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The I65T missense variant has most often been reported in association with mild phenylketonuria (PKU) phenotype and tetrahydrobiopterin (BH4) responsiveness (Pey et al., 2007; Zurfluh et al, 2008). However, it has also been identified in a number of patients with moderate or classic PKU, and in a BH4 unresponsive patient with a classic PKU phenotype (Couce et al., 2013). The I65T variant is located in the regulatory domain of the phenylalanine hydroxylase enzyme and has been associated with 27% to 60% residual phenylalanine hydroxylase activity (Couce et al., 2013). In summary, we interpret I65T as a pathogenic variant.
GeneReviews RCV000000668 SCV000324886 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America 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."
Invitae RCV000000668 SCV000629186 pathogenic Phenylketonuria 2018-11-28 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000000668 SCV000782446 pathogenic Phenylketonuria 2016-05-02 criteria provided, single submitter clinical testing
OMIM RCV000000668 SCV000020818 pathogenic Phenylketonuria 1992-01-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078516 SCV000888345 pathogenic not provided 2015-11-18 criteria provided, single submitter clinical testing

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