Submissions for variant NM_001360016.2(G6PD):c.407G>A (p.Arg136His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003868842	SCV004668212	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-06-04	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg136 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9332310, 18046504, 22164279, 30045279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with G6PD-related conditions. This variant is present in population databases (rs782205676, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 136 of the G6PD protein (p.Arg136His).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003868842	SCV005086516	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient hemolytic anemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected; however, some heterozygous female carriers can also be affected depending on X-inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygote(s), 2 hemizygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated coenzyme binding domain (PMID: 36353116). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. An alternative change of greater Grantham score (p.(Arg166Cys)) has been reported many times as likely pathogenic or pathogenic, and observed in individuals with G6PD deficiency and recurrent infections, or acute haemolytic crisis (ClinVar, PMID: 36353116). (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been observed in two hemizygous individuals with G6PD deficiency, and is otherwise known as the Naone variant (PMID: 7825590, PMID: 36212142). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Biochemical assays found this variant to significantly reduced enzyme activity (PMID: 7825590, PMID: 36212142). However, additional studies did not find this variant to have a significant affect (PMID: 33536406). (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign