Submissions for variant NM_001360016.2(G6PD):c.406C>T (p.Arg136Cys)

gnomAD frequency: 0.00002  dbSNP: rs979416826

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388767	SCV001589897	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-01-13	criteria provided, single submitter	clinical testing	This variant is also known as G6PD Valladolid. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1075240). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 9332310, 18046504, 22164279, 30045279). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 136 of the G6PD protein (p.Arg136Cys).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810730	SCV002048879	likely pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	The G6PD c.406C>T; p.Arg136Cys variant (rs979416826), also known as G6PD Valladolid, is reported in the literature in multiple individuals affected with G6PD deficiency and hemolytic anemia (Chen 2018, Kim 2011, Nuchprayoon 2008, Vaca 2003, Zarza 1997). This variant has been reported as a class II variant (Vaca 2003, Zarza 1997) but has also been reported in a hemizygous individual with G6PD enzyme activity consistent with a class III variant (Kim 2011). This variant is also reported in ClinVar (Variation ID: 1075240). This variant is found in the general population with an overall allele frequency of 0.002% (4/183369 alleles, including 2 hemizygotes) in the Genome Aggregation Database. The arginine at codon 136 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). Based on available information, this variant is considered to be likely pathogenic. References: Chen Y et al. Mutation of glucose-6-phosphate dehydrogenase deficiency in Chinese Han children in eastern Fujian. Medicine (Baltimore). 2018 Jul;97(30):e11553. PMID: 30045279. Kim S et al. Performance of the CareStart™ G6PD deficiency screening test, a point-of-care diagnostic for primaquine therapy screening. PLoS One. 2011;6(12):e28357. PMID: 22164279. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar. J Hum Genet. 2008;53(1):48-54. PMID: 18046504. Vaca G et al. Glucose-6-phosphate dehydrogenase (G-6-PD) mutations in Mexico: four new G-6-PD variants. Blood Cells Mol Dis. 2003 Jul-Aug;31(1):112-20. PMID: 12850494. Zarza R et al. Two new mutations of the glucose-6-phosphate dehydrogenase (G6PD) gene associated with haemolytic anaemia: clinical, biochemical and molecular relationships. Br J Haematol. 1997 Sep;98(3):578-82. PMID: 9332310.
Mendelics	RCV001388767	SCV002516420	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV001388767	SCV002599330	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency and anemia (PS4_M, PP4). Decreased activity in red blood cells (7-30%) (PS3). In silico analyses predict disruption of function (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
CeGaT Center for Human Genetics Tuebingen	RCV001810730	SCV002822057	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	G6PD: PM2, PS4:Moderate, PP4, PS3:Supporting
Revvity Omics, Revvity	RCV001388767	SCV003833821	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469744	SCV004195392	pathogenic	Malaria, susceptibility to	2023-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001810730	SCV005197995	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing