NM_000277.3(PAH):c.932T>C (p.Leu311Pro) AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Feb 22, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000000608.11

Allele description [Variation Report for NM_000277.3(PAH):c.932T>C (p.Leu311Pro)]

NM_000277.3(PAH):c.932T>C (p.Leu311Pro)

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.932T>C (p.Leu311Pro)
HGVS:
  • NC_000012.12:g.102846932A>G
  • NG_008690.2:g.116479T>C
  • NM_000277.3:c.932T>CMANE SELECT
  • NM_001354304.2:c.932T>C
  • NP_000268.1:p.Leu311Pro
  • NP_001341233.1:p.Leu311Pro
  • NC_000012.11:g.103240710A>G
  • NM_000277.1:c.932T>C
  • NM_000277.2(PAH):c.932T>C
  • P00439:p.Leu311Pro
Protein change:
L311P; LEU311PRO
Links:
UniProtKB: P00439#VAR_000996; OMIM: 612349.0003; dbSNP: rs62642936
NCBI 1000 Genomes Browser:
rs62642936
Molecular consequence:
  • NM_000277.3:c.932T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.932T>C - 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
SCV000020758OMIMno assertion criteria providedPathogenic
(Apr 19, 1988)
germlineliterature only

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

SCV000220931Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 2, 2014)
unknownliterature only

PubMed (15)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV001339028Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 13, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001370846ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Feb 22, 2020)
germlinecuration

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001583222Invitaecriteria provided, single submitter
Pathogenic
(Sep 24, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Analysis of the phenylalanine hydroxylase gene in the Spanish population: mutation profile and association with intragenic polymorphic markers.

PĂ©rez B, Desviat LR, Ugarte M.

Am J Hum Genet. 1997 Jan;60(1):95-102.

PubMed [citation]
PMID:
8981952
PMCID:
PMC1712559

Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.

Shi Z, Sellers J, Moult J.

Proteins. 2012 Jan;80(1):61-70. doi: 10.1002/prot.23159. Epub 2011 Sep 21.

PubMed [citation]
PMID:
21953985
PMCID:
PMC4170182
See all PubMed Citations (22)

Details of each submission

From OMIM, SCV000020758.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a German patient with phenylketonuria (PKU; 261600), Lichter-Konecki et al. (1988) found a novel restriction fragment pattern with the restriction endonuclease MspI, and showed by molecular cloning and DNA sequencing that the variation was created by a T-to-C transition in exon 9, resulting in a leu311-to-pro (L311P) substitution.

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

From Counsyl, SCV000220931.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (15)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339028.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: PAH c.932T>C (p.Leu311Pro) 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 allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). c.932T>C has been reported in the literature in multiple individuals in affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Rivera_2000, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least two in vitro studies report this variant has an impact on protein function and results in <10% of normal PAH activity. 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

From ClinGen PAH Variant Curation Expert Panel, SCV001370846.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (8)

Description

The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3.

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

From Invitae, SCV001583222.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces leucine with proline at codon 311 of the PAH protein (p.Leu311Pro). The leucine residue is highly conserved and there is a moderately physicochemical difference between leucine and proline. This variant is present in population databases (rs62642936, ExAC 0.001%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 9359039, 21871829, 2840952, 9634518, 10394930). ClinVar contains an entry for this variant (Variation ID: 578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. Experimental studies have shown that this variant affects PAH protein function (PMID: 12655546, 17935162, 30037505). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Aug 27, 2021

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