Submissions for variant NM_000277.3(PAH):c.281TCA[1] (p.Ile95del)

dbSNP: rs62508727

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000635	SCV001250569	pathogenic	Phenylketonuria	2019-10-18	reviewed by expert panel	curation	This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate.
Eurofins Ntd Llc (ga)	RCV000078518	SCV000110374	pathogenic	not provided	2013-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000078518	SCV000239098	pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is inconsistent (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 25894915, 19292873, 25255367, 14722928, 1709636, 17935162, 26503515, 24705691, 26666653, 19194782, 18985011, 17096675, 16256386, 24368688, 23430918, 20217238, 30487145, 31028937, 30747360, 32668217, 31589614, 32853555)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078518	SCV000601712	pathogenic	not provided	2017-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000635	SCV000629189	pathogenic	Phenylketonuria	2024-01-02	criteria provided, single submitter	clinical testing	This variant, c.284_286del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ile95del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62508727, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 1709636, 14722928, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile94del. ClinVar contains an entry for this variant (Variation ID: 604). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000000635	SCV001251471	pathogenic	Phenylketonuria		criteria provided, single submitter	research	The PAH c.284_286delTCA (p.I95del) variant results in a deletion of a single amino acid and has been observed in homozygous and compound heterozygous state in individuals with phenylketonuria. This variant has previously been shown to result in a reduced affinity of the PAH enzyme for phenylalanine (PMID: 1709636; 18985011; 19292873; 25894915; 26666653).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000635	SCV001372242	pathogenic	Phenylketonuria	2020-06-15	criteria provided, single submitter	clinical testing	Variant summary: PAH c.284_286delTCA (p.Ile95del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes. c.284_286delTCA has been well reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Chien_2004, Daniele_2007, Caillaud_1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Maximal velocity/Km) due to a markedly decreased subtrate specificity (increased Km) for Phenylalanine (Caillaud_1991). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000000635	SCV004201357	pathogenic	Phenylketonuria	2024-02-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000000635	SCV004847268	pathogenic	Phenylketonuria	2023-02-06	criteria provided, single submitter	clinical testing	The p.Ile95del variant in PAH has been reported, in the homozygous and compound heterozygous state, in numerous (at least 10) individuals with PAH deficiency (phenylketonuria or hyperphenylalaninemia) (Li 2015 PMID: 26503515, Yan 2019 PMID: 30747360, Li 2008 PMID: 30050108, Schwoerer 2018 PMID: 29560316, Lee 2008 PMID: 18985011, Daniele 2009 PMID: 19292873, Ho 2014 PMID: 24368688, Chen 2015 PMID: 25894915, Jeannesson-Thivisol 2015 PMID: 26666653, Liu 2018 PMID: 29316886). It has also been classified as pathogenic on Oct 18, 2019 by the ClinGen PAH Variant Curation Expert Panel (Variation ID 604) and has been identified in 13/912 Amish and 5/68036 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is a deletion of 1 amino acid at position 95 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function as they show it results in a reduced affinity of the PAH enzyme for phenylalanine (Caillaud 1991 PMID: 1709636). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase (PAH) deficiency. ACMG/AMP criteria applied: PM3_Very strong, PM2_Supporting, PM4, PS3_Moderate.
Neuberg Centre For Genomic Medicine, NCGM	RCV000000635	SCV005061252	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	The observed inframe deletion variant c.284_286del (p.Ile95del) in PAH gene as been reported previously in multiple individuals affected with phenylketonuria (Schwoerer et al. 2018; Yan et al. 2019). In vitro expression studies showed that this variant produced very low levels of PAH activity (Caillaud et al. 1991; Li et al. 2015). The p.Ile95del variant is present with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Ile95del causes deletion of amino acid Isoleucine at position 95. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000000635	SCV000020785	pathogenic	Phenylketonuria	2007-08-15	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078518	SCV000119488	not provided	not provided		flagged submission	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078518	SCV000119489	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000635	SCV000485292	likely pathogenic	Phenylketonuria	2016-05-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000635	SCV001455112	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing