NM_000920.3(PC):c.3473G>A (p.Arg1158His) AND Pyruvate carboxylase deficiency

Clinical significance:Uncertain significance (Last evaluated: May 31, 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:
RCV000317908.2

Allele description [Variation Report for NM_000920.3(PC):c.3473G>A (p.Arg1158His)]

NM_000920.3(PC):c.3473G>A (p.Arg1158His)

Gene:
PC:pyruvate carboxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q13.2
Genomic location:
Preferred name:
NM_000920.3(PC):c.3473G>A (p.Arg1158His)
HGVS:
  • NC_000011.10:g.66848963C>T
  • NG_008319.1:g.114414G>A
  • NM_000920.3:c.3473G>A
  • NM_001040716.1:c.3473G>A
  • NP_000911.2:p.Arg1158His
  • NP_001035806.1:p.Arg1158His
  • NC_000011.9:g.66616434C>T
Protein change:
R1158H
Links:
dbSNP: rs149054698
NCBI 1000 Genomes Browser:
rs149054698
Molecular consequence:
  • NM_001040716.1:c.3473G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pyruvate carboxylase deficiency
Synonyms:
ATAXIA WITH LACTIC ACIDOSIS II; Pyruvate Carboxylase Deficiency Disease
Identifiers:
MedGen: C0034341; Orphanet: 3008; OMIM: 266150

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000373448Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jun 14, 2016)
germlineclinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000817397Invitaecriteria provided, single submitter
Uncertain significance
(May 31, 2018)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000373448.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000817397.1

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

Description

This sequence change replaces arginine with histidine at codon 1158 of the PC protein (p.Arg1158His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs149054698, ExAC 0.006%). This variant has not been reported in the literature in individuals with PC-related disease. ClinVar contains an entry for this variant (Variation ID: 305615). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Mar 30, 2019

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