NM_001360016.2(G6PD):c.193A>G (p.Thr65Ala) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 12, 2022
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:: RCV000688144.11

Allele description [Variation Report for NM_001360016.2(G6PD):c.193A>G (p.Thr65Ala)]

NM_001360016.2(G6PD):c.193A>G (p.Thr65Ala)

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.193A>G (p.Thr65Ala)

Other names:

G6PD Mexico DF

HGVS:

NC_000023.11:g.154536011T>C
NG_009015.2:g.16562A>G
NM_000402.4:c.283A>G
NM_001042351.3:c.193A>G
NM_001360016.2:c.193A>GMANE SELECT
NP_000393.4:p.Thr95Ala
NP_001035810.1:p.Thr65Ala
NP_001346945.1:p.Thr65Ala
NC_000023.10:g.153764226T>C
NM_001042351.1:c.193A>G
NM_001042351.2:c.193A>G

Protein change:

T65A

Links:

dbSNP: rs199474830

NCBI 1000 Genomes Browser:

rs199474830

Molecular consequence:

NM_000402.4:c.283A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.193A>G - 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
SCV000815746	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 4, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599169	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Likely pathogenic (Aug 12, 2022)	unknown	curation	PubMed (3) [See all records that cite these PMIDs] 25189226, 30096395, 29300386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000815746

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 4, 2018)

germline

clinical testing

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

SCV002599169

Dunham Lab, University of Washington

criteria provided, single submitter

(Bayesian ACMG Guidelines, 2018)

Likely pathogenic
(Aug 12, 2022)

unknown

curation

PubMed (3)
[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	unknown	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Glucose-6-phosphate dehydrogenase deficiency in northern Mexico and description of a novel mutation.

García-Magallanes N, Luque-Ortega F, Aguilar-Medina EM, Ramos-Payán R, Galaviz-Hernández C, Romero-Quintana JG, Del Pozo-Yauner L, Rangel-Villalobos H, Arámbula-Meraz E.

J Genet. 2014 Aug;93(2):325-30.

PubMed [citation]

PMID:: 25189226

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000815746.4

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

Description

This sequence change replaces threonine with alanine at codon 65 of the G6PD protein (p.Thr65Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with G6PD deficiency (PMID:¬†25189226). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

From Dunham Lab, University of Washington, SCV002599169.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

Variant found in hemizygote with G6PD deficiency (PP4). Decreased activity in red blood cells of hemizygote and when expressed in E. coli (PS3). Not observed in gnomAD (PM2). Polyphen predicts as probably damaging, and further structural investigation indicates disruption of beta-alpha-beta motif and NADP binding site (PP3). Post_P 0.975 (odds of pathogenicity 350.3, 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

Last Updated: Sep 29, 2024

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