NM_000402.4(G6PD):c.1466G>C (p.Arg489Pro) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Clinical significance:Pathogenic (Last evaluated: Mar 10, 2020)

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:
RCV001212765.3

Allele description [Variation Report for NM_000402.4(G6PD):c.1466G>C (p.Arg489Pro)]

NM_000402.4(G6PD):c.1466G>C (p.Arg489Pro)

Gene:
G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000402.4(G6PD):c.1466G>C (p.Arg489Pro)
Other names:
G6PD, ARG459PRO
HGVS:
  • NC_000023.11:g.154532269C>G
  • NG_009015.2:g.20304G>C
  • NM_000402.4:c.1466G>C
  • NM_001042351.3:c.1376G>C
  • NM_001360016.2:c.1376G>CMANE SELECT
  • NP_000393.4:p.Arg489Pro
  • NP_001035810.1:p.Arg459Pro
  • NP_001346945.1:p.Arg459Pro
  • NC_000023.10:g.153760484C>G
  • NM_001042351.1:c.1376G>C
  • NM_001042351.2:c.1376G>C
Protein change:
R459P; ARG459PRO
Links:
OMIM: 305900.0059; dbSNP: rs72554665
NCBI 1000 Genomes Browser:
rs72554665
Molecular consequence:
  • NM_000402.4:c.1466G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042351.3:c.1376G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360016.2:c.1376G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Synonyms:
Hemolytic anemia due to G6PD deficiency; Glucose-6-phosphate dehydrogenase deficiency; Favism, susceptibility to
Identifiers:
MedGen: C2720289; OMIM: 300908

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001367223Centre for Mendelian Genomics,University Medical Centre Ljubljanacriteria provided, single submitter
Pathogenic
(Aug 20, 2019)
unknownclinical testing

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

SCV001384362Invitaecriteria provided, single submitter
Pathogenic
(Mar 10, 2020)
germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Genetic heterogeneity of glucose-6-phosphate dehydrogenase deficiency revealed by single-strand conformation and sequence analysis.

CalabrĂ² V, Mason PJ, Filosa S, Civitelli D, Cittadella R, Tagarelli A, Martini G, Brancati C, Luzzatto L.

Am J Hum Genet. 1993 Mar;52(3):527-36.

PubMed [citation]
PMID:
8447319
PMCID:
PMC1682169
See all PubMed Citations (17)

Details of each submission

From Centre for Mendelian Genomics,University Medical Centre Ljubljana, SCV001367223.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3.

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

From Invitae, SCV001384362.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (16)

Description

This sequence change replaces arginine with proline at codon 459 of the G6PD protein (p.Arg459Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs72554665, ExAC 0.002%). This variant has been observed in several individuals affected with G6PD deficiency (PMID: 8447319, 9299858, 23365477). This variant is also known in the literature as Cosenza variant. ClinVar contains an entry for this variant (Variation ID: 10422). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg459 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1562739, 10643148, 2263506, 6714986, 26823837, 25775246, 25541721, 17726510, 20203002, 11499668, 8537082, 21446359). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2021

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