ClinVar Miner

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

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Total submissions: 10
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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
Invitae RCV000180546 SCV000768477 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-11-01 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 RCV001000058 SCV000885496 pathogenic not specified 2019-05-14 criteria provided, single submitter clinical testing
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
LifeCell International Pvt. Ltd RCV000180546 SCV001443773 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing This variant in exon 9 of the G6PD gene results in the amino acid substitution from Alanine to Threonine at codon 365 (p.Ala365Thr) with the sequence change of c.1093G>A (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (3.8 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved in mammals and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.1093G>A; p.Ala365Thr variant, also referred to as c.1003G>A; p.Ala335Thr, commonly known as Chatham variant, causes class II of G6PD deficiency characterized by possessing less than 10% of normal enzyme activity, which makes it one of the most severe forms of G6PD deficiency (Gandomani et al. 2011; PMID:21677401). This variant has been reported in multiple individuals affected with glucose-6-phosphatedehydrogenase deficiency and is the second most common variant in several Middle-East countries and in some provinces of Iran (Kashmoola et al., 2015; PMID:25548459, Rahimi Z et al., 2006; PMID:16938474, Iwai et al., PMID:11499668). Experimental studies have shown that this missense change affects substrate affinity and stability of the glucose-6-phosphate dehydrogenase protein (Vulliamy et al., 1988; PMID:3393536)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000757321 SCV001500683 pathogenic not provided 2020-10-01 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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