ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.722G>A (p.Arg241His) (rs62508730)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000576386 SCV000852143 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518); PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster; PM5: R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters; PP4_Moderate: R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_Strong: R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup. (PMID:9429153). 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, PM5, PP4_Moderate, PM3_Strong).
GeneDx RCV000089055 SCV000239067 pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing The R241H variant in the PAH gene has been associated with approximately 25% residual phenylalanine hydroxylase enzyme activity and is also classified as a mild, BH4-responsive PAH variant as it has been associated with BH4-responsive, mild phenylketonuria (PKU) in patients compound heterozygous for R241H and a severe PAH pathogenic variant (Bénit et al. 1999; Danecka et al. 2015; Zurfluh et al. 2008).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089055 SCV000601716 pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576386 SCV000696461 pathogenic Phenylketonuria 2016-10-27 criteria provided, single submitter clinical testing Variant summary: The PAH c.722G>A (p.Arg241His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 12/121068 control chromosomes at a frequency of 0.0000991, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous affected individuals from various ethnicities, and has been shown experimentally to have 25% activity compared to wild-type. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000576386 SCV000834949 pathogenic Phenylketonuria 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 241 of the PAH protein (p.Arg241His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs62508730, ExAC 0.02%). This variant has been reported in combination with another PAH variant in individuals affected with hyperphenylalaninemia or phenylketonuria (PMID: 10479481, 26600521, 25894915, 22330942). ClinVar contains an entry for this variant (Variation ID: 102804). Experimental studies have shown that this missense change significantly reduces PAH enzyme activity (PMID: 10479481). A different missense substitution at this codon (p.Arg241Cys) has been determined to be pathogenic (PMID: 8222245, 19915519, 14681498, 18985011, 24368688, 16253218). This suggests that the arginine residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000576386 SCV001194105 pathogenic Phenylketonuria 2019-12-20 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.722G>A(R241H) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU HPA. Sources cited for classification include the following: PMID 17924342, 8659548, 23932990, 17096675, 24350308, 9634518, 21871829, 15171997, 10598814, 12655554, 19062537, 12655553, 18294361, 9429153, 18299955, 17935162 and 8268925. Classification of NM_000277.1(PAH):c.722G>A(R241H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089055 SCV000119660 not provided not provided no assertion provided not provided

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