ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.158G>A (p.Arg53His) (rs118092776)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000490373 SCV000852170 uncertain significance Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4: Detected in a patient with mild hyperphe (PMID:24401910); PM3: Detected with V388L (LP) (PMID:24401910). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4, PM3).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088842 SCV000119435 not provided not provided no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000088842 SCV000696438 uncertain significance not provided 2016-01-27 criteria provided, single submitter clinical testing Variant summary: c.158G>A affects a conserved nucleotide, resulting in amino acid change from Arg to His. 4/5 in-silico tools predict this variant to be damaging. This variant was found in 212/121382 control chromosomes at a frequency of 0.0017466, predominantly observed in East Asian subpopulation of ExAC with MAF of 0.01596 with one homozygote. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0079057), suggesting this variant might be a polymorphism in the East Asians. This variant has been reported in multiple affected patients (mostly East Asian ethnicity) with either PKU or mild HPA (Park_1998, Liang_2014, Tao_2015, and Jeannesson-Thivisol _2015). All 8 alleles reported by Tao_2015 had co-occurrence with a probably pathogenic variant c. 842+2T>A in cis. Among East Asian patients and controls tested, the variant is detected with allele frequencies of 12/492 and 138/8648 chromosomes, respectively. The difference is not statistically significant (p=0.22). In addition, the functional study showed that variant has 79% of in vitro activity relative to the wild type control (Liang_2014), which can explain the very mild (or lack) of phenotype of the individuals carrying this variant. One clinical laboratory (via ClinVar) classified this variant as VUS, without evidence to independently evaluate. Considering all, this variant was classified as variant of unknown significance until more information becomes available.
Invitae RCV000490373 SCV000754088 benign Phenylketonuria 2017-10-02 criteria provided, single submitter clinical testing
SingHealth Duke-NUS Institute of Precision Medicine RCV000490373 SCV000853180 likely benign Phenylketonuria 2017-06-07 no assertion criteria provided curation
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490373 SCV000267433 uncertain significance Phenylketonuria 2016-03-18 criteria provided, single submitter reference population

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