Submissions for variant NM_000402.4(G6PD):c.298T>C (p.Tyr100His)

gnomAD frequency: 0.00002  dbSNP: rs137852349

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lifecell International Pvt. Ltd	RCV001264782	SCV001443096	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	This variant in exon 4 of the G6PD gene results in the amino acid substitution from Tyrosine to Histidine at codon 100 (p.Tyr100His) with the sequence change of c.298T>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a moderate physicochemical difference between Tyrosine and Histidine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant lies in the Glucose-6-phosphate dehydrogenase, NAD binding domain of the Glucose-6-phosphate 1-dehydrogenase protein (http://pfam.xfam.org/family/G6PD_N). This is a Class II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. This variant is also known as G6PD Namoru in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Arunachalam AK et al., 2019 and Chalvam R., et al. 2007; PMID: 17233850, Ganczakowski M et al. 1995; PMID: 7825590.
Dunham Lab, University of Washington	RCV001264782	SCV002599323	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 (4-33%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001264782	SCV003445326	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 70 of the G6PD protein (p.Tyr70His). This variant is present in population databases (rs137852349, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD-related conditions (PMID: 7825590, 17233850, 33069889). ClinVar contains an entry for this variant (Variation ID: 10416). 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 disrupts the p.Tyr70 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7577654, 20621077, 21446359; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001264782	SCV003833798	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-04	criteria provided, single submitter	clinical testing
OMIM	RCV000011160	SCV000031387	other	G6PD NAMORU	2016-07-28	no assertion criteria provided	literature only