ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.1093G>A (p.Ala365Thr) (rs5030869)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000757321 SCV000233010 pathogenic not provided 2014-02-10 criteria provided, single submitter clinical testing
Counsyl RCV000180546 SCV000677960 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2015-06-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622381 SCV000742273 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000180546 SCV000768477 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 335 of the G6PD protein (p.Ala335Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs5030869, ExAC 0.07%). This variant has been reported in multiple individuals affected with glucose-6-phosphatedehydrogenase deficiency (PMID: 11499668, 16927025, 20602793, 21677401, 22293322, 25548459, 26060661). It has been associated with < 10% normal enzyme activity in red blood cells from affected individuals (PMID: 3393536, 12497642, 15315792). This variant is also known as the Chatham variant in the literature. ClinVar contains an entry for this variant (Variation ID: 10363). Experimental studies have shown that this missense change affects substrate affinity and stability of the glucose-6-phosphate dehydrogenase protein (PMID: 3393536). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757321 SCV000885496 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing The G6PD c.1003G>A; p.Ala335Thr variant (rs5030869), commonly known as G6PD Chatham, is one of the most common G6PD deficiency alleles worldwide and is considered a Class II variant with severe enzymatic deficiency (Gandomani 2011, Mesbah-Namin 2002, Vulliamy 1988). This variant is reported in ClinVar as pathogenic (Variation ID: 10363), and is observed in general population databases with overall allele frequencies of 0.0095 percent (1/10563 alleles) in the Exome Variant Server, and 0.02 percent (36/177946 alleles), including 24 hemizygotes in the Genome Aggregation Database. The alanine is moderately conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, G6PD Chatham is considered pathogenic. REFERENCES Link to ClinVar database for p.Ala335Thr: Gandomani MG et al. Molecular identification of G6PD Chatham (G1003A) in Khuzestan province of Iran. J Genet. 2011 Apr;90(1):143-5. Mesbah-Namin SA et al. Three major glucose-6-phosphate dehydrogenase-deficient polymorphic variants identified in Mazandaran state of Iran. Br J Haematol. 2002 Jun;117(3):763-4. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5.
Fulgent Genetics,Fulgent Genetics RCV000763202 SCV000893821 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000011081 SCV000031308 other G6PD CHATHAM 2017-05-24 no assertion criteria provided literature only
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000180546 SCV000891506 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2017-12-30 no assertion criteria provided curation

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