NM_001360016.2(G6PD):c.1132G>A (p.Gly378Ser) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 22, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002305724.4

Allele description [Variation Report for NM_001360016.2(G6PD):c.1132G>A (p.Gly378Ser)]

NM_001360016.2(G6PD):c.1132G>A (p.Gly378Ser)

Gene:

G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001360016.2(G6PD):c.1132G>A (p.Gly378Ser)

Other names:

G6PD Montpellier

HGVS:

NC_000023.11:g.154532722C>T
NG_009015.2:g.19851G>A
NM_000402.4:c.1222G>A
NM_001042351.3:c.1132G>A
NM_001360016.2:c.1132G>AMANE SELECT
NP_000393.4:p.Gly408Ser
NP_001035810.1:p.Gly378Ser
NP_001035810.1:p.Gly378Ser
NP_001346945.1:p.Gly378Ser
NC_000023.10:g.153760937C>T
NM_001042351.1:c.1132G>A
NM_001042351.2:c.1132G>A

Protein change:

G378S

Molecular consequence:

NM_000402.4:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.1132G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.1132G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Synonyms:: Hemolytic anemia due to G6PD deficiency; Favism, susceptibility to; Class I glucose-6-phosphate dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0010480; MedGen: C2720289; Orphanet: 466026; OMIM: 300908

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002599268	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Likely pathogenic (Aug 12, 2022)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 22139979, 29300386
SCV004299708	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22139979, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002599268

Dunham Lab, University of Washington

criteria provided, single submitter

(Bayesian ACMG Guidelines, 2018)

Likely pathogenic
(Aug 12, 2022)

unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV004299708

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 22, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.

Tavtigian SV, Greenblatt MS, Harrison SM, Nussbaum RL, Prabhu SA, Boucher KM, Biesecker LG; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI)..

Genet Med. 2018 Sep;20(9):1054-1060. doi: 10.1038/gim.2017.210. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300386
PMCID:: PMC6336098

Practical approach for characterization of glucose 6-phosphate dehydrogenase (G6PD) deficiency in countries with population ethnically heterogeneous: description of seven new G6PD mutants.

Moradkhani K, Mekki C, Bahuau M, Te VL, Holder M, Pissard S, Préhu C, Rose C, Wajcman H, Galactéros F.

Am J Hematol. 2012 Feb;87(2):208-10. doi: 10.1002/ajh.22218. Epub 2011 Dec 3.

PubMed [citation]

PMID:: 22139979

See all PubMed Citations (3)

Details of each submission

From Dunham Lab, University of Washington, SCV002599268.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

Variant found in hemizygote with G6PD deficiency and no other symptoms (PP4). Decreased activity in red blood cells (50%) (PS3).Below expected carrier frequency in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299708.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 378 of the G6PD protein (p.Gly378Ser). This variant is present in population databases (rs371489738, gnomAD 0.003%). This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 22139979). This variant is also known as G6PD Montpellier. ClinVar contains an entry for this variant (Variation ID: 1722614). 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 G6PD protein function. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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