ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.721C>T (p.Arg241Cys) (rs76687508)

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Total submissions: 10
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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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089054 SCV000203183 pathogenic not provided 2016-07-28 criteria provided, single submitter clinical testing
GeneDx RCV000089054 SCV000239066 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing The R241C variant has most commonly been associated with mild hyperphenylalaninemia or mildphenylketonuria (PKU), although it has also been reported in an individual with classic PKU (Chien etal., 2004; Lee et al., 2008; Liang et al., 2014). This variant is a common pathogenic variant in theTaiwanese and accounts for approximately 33% of pathogenic alleles in this population (Liang et al.,2014). The R241C variant is associated with significant residual phenylalanine hydroxylase enzymeactivity and has been classified as responsive to tetrahydrobiopterin (BH4) therapy (Liang et al.,2014; Zurfluh et al., 2008).
Counsyl RCV000153635 SCV000485392 pathogenic Phenylketonuria 2016-09-09 criteria provided, single submitter clinical testing
Invitae RCV000153635 SCV000629209 pathogenic Phenylketonuria 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 241 of the PAH protein (p.Arg241Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs76687508, ExAC 0.1%). This variant has been reported as homozygous or compound heterozygous in multiple individuals affected with PAH-related diseases with evidence of segregation (PMID: 8222245, 19915519, 14681498, 18985011, 24368688, Invitae). This variant is known to be associated with BH4 responsiveness in affected individuals (PMID: 26322415, 11486900, 18985011). ClinVar contains an entry for this variant (Variation ID: 102803). Experimental studies have shown that this variant causes partial deficiency (~28% of wild type) of enzymatic activity in vitro (PMID: 16253218). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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 Praxis fuer Humangenetik Tuebingen RCV000089054 SCV001370958 pathogenic not provided 2020-05-01 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

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