Submissions for variant NM_000402.4(G6PD):c.653C>T (p.Ser218Phe) (rs5030868)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000079409	SCV000231598	pathogenic	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences	RCV000179363	SCV000236525	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2014-02-14	criteria provided, single submitter	clinical testing
UCLA Clinical Genomics Center, UCLA	RCV000179363	SCV000255508	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2013-08-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000079409	SCV000321681	pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing	The S188F variant in the G6PD gene has been reported numerous times in association with glucose-6-phosphate dehydrogenase deficiency and is commonly found in individuals of mediterranean and middle eastern ancestry (for examples, see Vulliamy et al., 1988; Kurdi-Haidar et al., 1990; Kashmoola et al., 2015). The S188F variant is also associated with acute hemolytic anemia (Vulliamy et al., 1988). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with the S188F variant, increased affinity for G6P and decreased in vitro thermostability (Vulliamy et al., 1988). Based on currently available evidence, we interpret S188F as a pathogenic variant.
Invitae	RCV000179363	SCV000647802	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 188 of the G6PD protein (p.Ser188Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs5030868, ExAC 1.6%). This variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent, being reported in 60-96% of biochemically diagnosed individuals (PMID: 8611726, 15315792, 16119988, 1978554, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Experimental studies show that this variant causes protein instability and results in reduced G6PD enzymatic activity in red blood cells of the patients (PMID: 22906047, 24460025, 3393536). In summary, this variant is the most common G6PD deficiency variant in many populations and has been shown to affect protein activity. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000179363	SCV000677998	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2015-06-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623137	SCV000741900	likely pathogenic	Inborn genetic diseases	2016-12-14	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000079409	SCV000885494	pathogenic	not provided	2017-10-18	criteria provided, single submitter	clinical testing	The G6PD c.563C>T; p.Ser188Phe variant, also known as G6PD Mediterranean, has been reported in multiple patients diagnosed with hemolytic anemia and/or hyperbilirubinema (Moiz 2012, Vulliamy 1988). Functional characterization of red blood cells with G6PD Mediterranean indicates a significant decrease of enzymatic activity (class II pathogenic variant), and decreased heat stability (Kirkman 1964, Moiz 2012, Morelli 1984, Vulliamy 1988). Kirkman H et al. Functionally abnormal Glucose 6-Phosphate Dehydrogenases. Cold Spring Harb Symp Quant Biol. 1964; 29:391-8. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012; 12:126. Morelli A et al. G6PD Cagliari: a new low activity glucose 6-phosphate dehydrogenase variant characterized by enhanced intracellular lability. Hum Genet. 1984; 66(1):62-5. Vulliamy T 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; 85(14):5171-5.
Fulgent Genetics,Fulgent Genetics	RCV000477810	SCV000893824	pathogenic	Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000445579	SCV000915299	pathogenic	Glucose 6 phosphate dehydrogenase deficiency	2018-10-19	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the G6PD c.563C>T (p.Ser188Phe) variant, also called G6PD Mediterranean, has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (Hellani et al. 2009; Moiz et al. 2012; Santana et al. 2013; Molou et al. 2014 and Jamornthanyawat et al. 2014). The p.Ser188Phe variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The p.Ser188Phe variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (Vulliamy et al. 1988). Based on the collective evidence, the p.Ser188Phe variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM	RCV000011086	SCV000031313	other	G6PD MEDITERRANEAN	2018-05-11	no assertion criteria provided	literature only
OMIM	RCV000011087	SCV000031314	other	G6PD SASSARI	2018-05-11	no assertion criteria provided	literature only
OMIM	RCV000011088	SCV000031315	other	G6PD CAGLIARI	2018-05-11	no assertion criteria provided	literature only
FirmaLab	RCV000445579	SCV000106042	pathogenic	Glucose 6 phosphate dehydrogenase deficiency		no assertion criteria provided	clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000477810	SCV000536869	pathogenic	Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2016-05-31	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City	RCV000179363	SCV000854728	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-07-14	no assertion criteria provided	clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman	RCV000761429	SCV000891507	uncertain significance	Angioedema induced by ACE inhibitors, susceptibility to	2017-12-30	no assertion criteria provided	curation