NM_000277.3(PAH):c.320A>G (p.His107Arg) AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Dec 9, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000210807.5

Allele description [Variation Report for NM_000277.3(PAH):c.320A>G (p.His107Arg)]

NM_000277.3(PAH):c.320A>G (p.His107Arg)

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.320A>G (p.His107Arg)
HGVS:
  • NC_000012.12:g.102894767T>C
  • NG_008690.2:g.68644A>G
  • NM_000277.3:c.320A>GMANE SELECT
  • NM_001354304.2:c.320A>G
  • NP_000268.1:p.His107Arg
  • NP_001341233.1:p.His107Arg
  • NC_000012.11:g.103288545T>C
  • NM_000277.1:c.320A>G
Protein change:
H107R
Links:
dbSNP: rs542645236
NCBI 1000 Genomes Browser:
rs542645236
Molecular consequence:
  • NM_000277.3:c.320A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.320A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Phenylketonuria (PKU)
Synonyms:
Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:
MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000266851Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospitalno assertion criteria providedLikely pathogenic
(Oct 1, 2013)
paternalclinical testing

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

Citation Link,

SCV000791589Counsylcriteria provided, single submitter
Likely pathogenic
(May 13, 2017)
unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV001163352Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001223781Invitaecriteria provided, single submitter
Pathogenic
(Aug 25, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001572860ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Dec 9, 2020)
germlinecuration

Citation Link

Description

This variant was reported to be a novel likely pathogenic mutation for the first time by us.

SCV000266851

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
Chinesepaternalyes11not provided70not providedclinical testing

Citations

PubMed

Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing.

Li N, Jia H, Liu Z, Tao J, Chen S, Li X, Deng Y, Jin X, Song J, Zhang L, Liang Y, Wang W, Zhu J.

Sci Rep. 2015 Oct 27;5:15769. doi: 10.1038/srep15769.

PubMed [citation]
PMID:
26503515
PMCID:
PMC4621502

[Mutational spectrum of phenylalanine hydroxylase gene and identification of novel mutations in patients with hyperphenylalaninemia in Jiangsu province].

Zhang JJ, Sun Y, Sun YJ, Huang ML, Zhang J, Liang XW, Jiang T, Xu ZF.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2013 Oct;30(5):513-7. doi: 10.3760/cma.j.issn.1003-9406.2013.05.002. Chinese.

PubMed [citation]
PMID:
24078561
See all PubMed Citations (10)

Details of each submission

From Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, SCV000266851.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Chinese1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyes70not providednot provided1not provided1not provided

From Counsyl, SCV000791589.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163352.1

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

From Invitae, SCV001223781.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces histidine with arginine at codon 107 of the PAH protein (p.His107Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs542645236, ExAC 0.001%). This variant has been observed in individuals with PAH-related disease (PMID: 26600521, 30050108, 25456745, 29390883, 21307867). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225134). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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

From ClinGen PAH Variant Curation Expert Panel, SCV001572860.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4.

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

Last Updated: Aug 7, 2021

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