Submissions for variant NM_000402.4(G6PD):c.1114C>T (p.Leu372Phe)

gnomAD frequency: 0.00003  dbSNP: rs137852342

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079389	SCV000111268	uncertain significance	not provided	2012-12-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000079389	SCV000885493	likely pathogenic	not provided	2017-07-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000991013	SCV001142104	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000991013	SCV001513322	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 342 of the G6PD protein (p.Leu342Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 8364584, 10502785, 16329560, 20203002, 30045279, 30315739). This variant is also known as C13184T or Chinese-5. ClinVar contains an entry for this variant (Variation ID: 10405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Dunham Lab, University of Washington	RCV000991013	SCV002599355	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, some with anemia (PS4_M, PP4). Also found in two heterozygous sisters with deficiency who inherited this variant (c.1024C>T) from father and c.383T>C from mother (PP1). Decreased activity in red blood cells (2-39%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
Revvity Omics, Revvity	RCV000991013	SCV003833854	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526593	SCV005040243	pathogenic	Niemann-Pick disease, type C	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in 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 1.6e-05 in 251162 control chromosomes. c.1114C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004540994	SCV005040778	pathogenic	Metachromatic leukodystrophy	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250080 control chromosomes. c.1114C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Biffi_2008, Heinisch_1995, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579517	SCV005062072	pathogenic	G6PD deficiency	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.1114C>T (p.Leu372Phe, also known as Chinese-5) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (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 0.00014 in 183026 control chromosomes with 7 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00014 vs 0.29), allowing no conclusion about variant significance. c.1114C>T has been reported in the literature in many individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example, Wang_2021, Fu_2018). These data indicate that the variant is very likely to be associated with disease. At least 7 studies report experimental evidence evaluating an impact on protein function using hemizygote cells, the average G6PD activity appeared to be 30-40% of normal activity (Geck_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29339739, 36681081, 34659341). ClinVar contains an entry for this variant (Variation ID: 10405). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011148	SCV000031375	other	G6PD MAHIDOL-LIKE	2013-04-18	no assertion criteria provided	literature only