NM_000277.3(PAH):c.158G>A (p.Arg53His) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Mar 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000088842.2

Allele description [Variation Report for NM_000277.3(PAH):c.158G>A (p.Arg53His)]

NM_000277.3(PAH):c.158G>A (p.Arg53His)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.158G>A (p.Arg53His)
Other names:
NM_000277.2(PAH):c.158G>A
HGVS:
  • NC_000012.12:g.102912801C>T
  • NG_008690.2:g.50610G>A
  • NM_000277.3:c.158G>A
  • NM_001354304.2:c.158G>A
  • NP_000268.1:p.Arg53His
  • NP_001341233.1:p.Arg53His
  • NC_000012.11:g.103306579C>T
  • NM_000277.1:c.158G>A
  • NM_000277.2:c.158G>A
  • P00439:p.Arg53His
Protein change:
R53H
Links:
UniProtKB: P00439#VAR_000878; dbSNP: rs118092776
NCBI 1000 Genomes Browser:
rs118092776
Molecular consequence:
  • NM_000277.3:c.158G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.158G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000119435DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTEno assertion providednot providednot providednot provided

SCV000696438Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Uncertain significance
(Jan 27, 2016)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000754088Invitaecriteria provided, single submitter
Benign
(Mar 4, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providednot providednot providednot providednot providednot provided1not providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria.

Tao J, Li N, Jia H, Liu Z, Li X, Song J, Deng Y, Jin X, Zhu J.

Pediatr Res. 2015 Dec;78(6):691-9. doi: 10.1038/pr.2015.167. Epub 2015 Aug 31.

PubMed [citation]
PMID:
26322415
PMCID:
PMC4700046

The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population.

Liang Y, Huang MZ, Cheng CY, Chao HK, Fwu VT, Chiang SH, Hsiao KJ, Niu DM, Su TS.

J Hum Genet. 2014 Mar;59(3):145-52. doi: 10.1038/jhg.2013.136. Epub 2014 Jan 9.

PubMed [citation]
PMID:
24401910
See all PubMed Citations (4)

Details of each submission

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119435.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From Integrated Genetics/Laboratory Corporation of America, SCV000696438.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000754088.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 10, 2020

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