NM_000277.3(PAH):c.770G>T (p.Gly257Val) AND Phenylketonuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 2, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000668413.2

Allele description [Variation Report for NM_000277.3(PAH):c.770G>T (p.Gly257Val)]

NM_000277.3(PAH):c.770G>T (p.Gly257Val)

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.770G>T (p.Gly257Val)
HGVS:
  • NC_000012.12:g.102852887C>A
  • NG_008690.2:g.110524G>T
  • NM_000277.3:c.770G>TMANE SELECT
  • NM_001354304.2:c.770G>T
  • NP_000268.1:p.Gly257Val
  • NP_001341233.1:p.Gly257Val
  • NC_000012.11:g.103246665C>A
  • NM_000277.1:c.770G>T
Protein change:
G257V
Links:
dbSNP: rs62642908
NCBI 1000 Genomes Browser:
rs62642908
Molecular consequence:
  • NM_000277.3:c.770G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.770G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000793007Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 25, 2017)
unknownclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV000919916Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Pathogenic
(Aug 2, 2018)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles.

Dobrowolski SF, Ellingson C, Coyne T, Grey J, Martin R, Naylor EW, Koch R, Levy HL.

Mol Genet Metab. 2007 Jul;91(3):218-27. Epub 2007 May 14.

PubMed [citation]
PMID:
17502162

Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation.

Chien YH, Chiang SC, Huang A, Chou SP, Tseng SS, Huang YT, Hwu WL.

Hum Mutat. 2004 Feb;23(2):206.

PubMed [citation]
PMID:
14722928
See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000793007.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Integrated Genetics/Laboratory Corporation of America, SCV000919916.1

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

Description

Variant summary: PAH c.770G>T (p.Gly257Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246102 control chromosomes (in gnomAD). c.770G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Liang 2014, Li 2015, Liu 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Liang 2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: May 1, 2021

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