Submissions for variant NM_000277.3(PAH):c.721C>T (p.Arg241Cys)

gnomAD frequency: 0.00009  dbSNP: rs76687508

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000153635	SCV000852164	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). 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: (PM2, PP3, PP4_Moderate, PM3_Strong, PS3).
Eurofins Ntd Llc (ga)	RCV000089054	SCV000203183	pathogenic	not provided	2016-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000089054	SCV000239066	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Associated with mild hyperphenylalaninemia or mild phenylketonuria (PKU), although it has also been reported in an individual with classic PKU (Chien et al., 2004; Lee et al., 2008; Liang et al., 2014); R241C is associated with reduced residual PAH enzyme activity (Liang et al., 2014); 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: 11486900, 25750018, 9860305, 18985011, 9634518, 8222245, 14722928, 27264808, 29499199, 29317692, 11243094, 29961769, 30678510, 30747360, 30275481, 34426522, 33677757, 32668217, 32778825, 30037505, 17935162, 24401910, 31053953)
Counsyl	RCV000153635	SCV000485392	pathogenic	Phenylketonuria	2016-09-09	criteria provided, single submitter	clinical testing
Invitae	RCV000153635	SCV000629209	pathogenic	Phenylketonuria	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 241 of the PAH protein (p.Arg241Cys). This variant is present in population databases (rs76687508, gnomAD 0.1%). This missense change has been observed in individuals with PAH-related diseases (PMID: 8222245, 11486900, 14681498, 18985011, 19915519, 24368688, 26322415; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 102803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 16253218). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153635	SCV000696460	pathogenic	Phenylketonuria	2016-03-25	criteria provided, single submitter	clinical testing	Variant summary: The c.721C>T variant affects a conserved nucleotide, resulting in amino acid change from Arg to Cys located at catalytic domain of the protein. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 17/120962 control chromosomes in the heterozygous state from the large and broad populations of ExAC at a frequency of 0.0001405, which does not exceed the maximal expected frequency of a pathogenic allele (0.0079057) in this gene. This variant is found in several patients with phenylketonuria with concordant recessive genotypes and is reported to be the most common mild pathogenic variant in the Taiwanese population. Functional studies are concordant with impairment of enzymatic activity. Multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000153635	SCV001163721	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000089054	SCV001370958	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PP3
3billion	RCV000153635	SCV002573293	pathogenic	Phenylketonuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15319459 , 7915167). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11142755). A different missense change at the same codon (p.Arg241His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102804). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000153635	SCV002795331	pathogenic	Phenylketonuria	2021-12-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000153635	SCV003824289	pathogenic	Phenylketonuria	2021-12-02	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089054	SCV000119659	not provided	not provided		no assertion provided	not provided
SingHealth Duke-NUS Institute of Precision Medicine	RCV000153635	SCV000853108	pathogenic	Phenylketonuria	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000153635	SCV001453115	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000089054	SCV001927095	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000089054	SCV001959600	pathogenic	not provided		no assertion criteria provided	clinical testing