Submissions for variant NM_000277.3(PAH):c.113TCT[1] (p.Phe39del)

dbSNP: rs199475565

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169302	SCV004222633	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	This c.113_115TCTdel (p.Phe39del) variant is also known as c.115_117delTTC (p.Phe39del) in the literature. This variant in PAH was reported in 3 Chinese patients with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in 5 patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 16256386, 23500595, 26542770, 29102225, 12655550). This variant is present in European (non-Finnish) populations at a frequency of 0.000035 (gnomAD), and in European (non-Finnish) populations at a frequency of 0.000045 (ExAC). This variant changes the protein length from an in-frame deletion in a non-repetitive region. Functional analysis of this variant found that it is associated with approximately 20% residual enzyme activity (PMID: 11161839; 17935162). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP4_moderate, PM4, PS3-supporting, PM3_strong.
Counsyl	RCV000169302	SCV000220621	likely pathogenic	Phenylketonuria	2014-08-22	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000186077	SCV000227084	pathogenic	not provided	2014-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000186077	SCV000239099	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Gjetting et al., 2001; Zurfluh et al, 2008); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27121329, 26503515, 23430918, 34828281, 23500595, 17935162, 8406445, 18294361, 21147011, 28676969, 29499199, 34440436, 31589614, 32668217, 28182360, 35405047, 36246604, 11161839)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169302	SCV000917931	pathogenic	Phenylketonuria	2018-11-23	criteria provided, single submitter	clinical testing	Variant summary: PAH c.116_118delTCT (p.Phe39del) results in an in-frame deletion that is predicted to remove a Phe amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 246172 control chromosomes. c.116_118delTCT has been reported in the literature in multiple individuals affected with classic and mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and mild hyperphenylalaninemia (Aldamiz-Echevarria_2016 and Zurfluh_2008). The variant was indicated to have 20% PAH enzyme activity (Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169302	SCV000932924	pathogenic	Phenylketonuria	2024-07-07	criteria provided, single submitter	clinical testing	This variant, c.116_118del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Phe39del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762462102, gnomAD 0.004%). This variant has been observed in individual(s) with phenylketonuria (PMID: 9452062, 12655550, 16256386, 19394257, 23500595, 26210745, 26542770). This variant is also known as DF39. ClinVar contains an entry for this variant (Variation ID: 188933). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Phe39 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 206386, 8592329, 8659548, 12655544, 12655553, 17935162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000186077	SCV001250402	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	PAH: PS4, PM2, PM3, PM4, PP4, PS3:Supporting
Revvity Omics, Revvity	RCV000169302	SCV002016492	pathogenic	Phenylketonuria	2020-10-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169302	SCV002808255	likely pathogenic	Phenylketonuria	2021-09-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169302	SCV004201373	pathogenic	Phenylketonuria	2024-02-22	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169302	SCV005051896	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000186077	SCV000119358	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169302	SCV002088679	pathogenic	Phenylketonuria	2021-06-23	no assertion criteria provided	clinical testing