Submissions for variant NM_001360016.2(G6PD):c.703C>T (p.Leu235Phe)

gnomAD frequency: 0.00002  dbSNP: rs782757170

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV002249999	SCV002516415	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV002249999	SCV002599221	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in hemizygote with G6PD deficiency (PP4). Decreased activity in red blood cells (PS3). Below expected carrier frequency in gnomAD (PM2). Interpreted as pathogenic by Mendelics (PP5). Post_P 0.975 (odds of pathogenicity 350.3, Prior_P 0.1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235690	SCV003934494	uncertain significance	not specified	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.793C>T (p.Leu265Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal (IPR022675) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 205125 control chromosomes, including two hemizygotes in gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.793C>T has been reported in the literature in an individual (hemizygote) affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example: Yan_2006). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36315991, 17018380). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002249999	SCV005823803	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 235 of the G6PD protein (p.Leu235Phe). This variant is present in population databases (rs782757170, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with G6PD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1685832). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.