Submissions for variant NM_000402.4(G6PD):c.770G>A (p.Arg257Gln)

gnomAD frequency: 0.00008  dbSNP: rs137852328

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000765	SCV001157816	pathogenic	not specified	2018-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001168393	SCV001330978	uncertain significance	G6PD deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851785	SCV002234925	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the G6PD protein (p.Arg227Gln). This variant is present in population databases (rs137852328, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1611091). This variant is also known as G6PD Mexico City. ClinVar contains an entry for this variant (Variation ID: 10395). 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. Experimental studies have shown that this missense change affects G6PD function (PMID: 25407525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg227 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been observed in individuals with G6PD-related conditions (PMID: 10571945), which suggests that this may be a clinically significant amino acid residue. 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.
Mendelics	RCV001851785	SCV002516417	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV001851785	SCV002599343	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in hemizygote with deficiency (PP4). Decreased activity in red blood cells (35%) (PS3). Affects same amino acid as pathogenic 227R>L (ClinVar ID 10387) (PM5). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by ARUP Laboratories (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
OMIM	RCV000011131	SCV000031358	other	G6PD MEXICO CITY	2017-05-24	no assertion criteria provided	literature only