Submissions for variant NM_000277.3(PAH):c.*19G>T

gnomAD frequency: 0.00103  dbSNP: rs372637021

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000538868	SCV001146700	uncertain significance	Phenylketonuria	2019-09-27	reviewed by expert panel	curation	The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1.
PreventionGenetics, part of Exact Sciences	RCV000252084	SCV000303440	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000252084	SCV000521187	likely benign	not specified	2017-08-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000252084	SCV000601704	likely benign	not specified	2017-07-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538868	SCV000629166	benign	Phenylketonuria	2023-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000538868	SCV000788498	uncertain significance	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000252084	SCV000917925	likely benign	not specified	2023-01-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.*19G>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0022 in 252634 control chromosomes (gnomAD, da Silva_2003, Alibakhshi_2022), predominantly at a frequency of 0.0081 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. This frequency is slightly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0081 vs 0.0079), suggesting this variant is likely a benign polymorphism found primarily in South Asians. The variant has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (da Silva_2003, Trunzo_2015). However, co-occurrence with another pathogenic variant (in cis) has been reported (PAH c.1223G>A, p.R408Q), providing supporting evidence for a benign role (Trunzo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: three submitters (including one expert panel) classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000538868	SCV001737223	uncertain significance	Phenylketonuria	2021-05-18	criteria provided, single submitter	clinical testing