Submissions for variant NM_024996.7(GFM1):c.748C>T (p.Arg250Trp)

gnomAD frequency: 0.00001  dbSNP: rs139430866

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000023564	SCV000680244	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2017-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000800330	SCV000940038	pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 250 of the GFM1 protein (p.Arg250Trp). This variant is present in population databases (rs139430866, gnomAD 0.009%). This missense change has been observed in individual(s) with GFM1-related disease (PMID: 21119709, 28216230). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30598). 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) has been performed at Invitae 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 GFM1 protein function. For these reasons, this variant has been classified as Pathogenic.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156063	SCV003845283	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000800330	SCV003936349	likely pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 21119709, 34277617, 28216230)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023564	SCV004029719	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: GFM1 c.748C>T (p.Arg250Trp) results in a non-conservative amino acid change located in the Translational (tr)-type GTP-binding domain (IPR000795) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251440 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in GFM1 causing Combined Oxidative Phosphorylation Deficiency 1 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.748C>T has been reported in the literature in individuals affected with features of Combined Oxidative Phosphorylation Deficiency 1, including in trans with another disease-causing variant in at-least two siblings and in the homozygous state in at-least one affected individual (example: Smits_2011, Simon_2017). These data indicate that the variant is 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 absence of normal GFM1 protein in fibroblasts from patients, which can be rescued by over-expressing normal GFM1 (Smits_2011). The following publications have been ascertained in the context of this evaluation (PMID: 28216230, 21119709). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic: n=3; likely pathogenic: n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000023564	SCV004199288	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2023-11-06	criteria provided, single submitter	clinical testing
OMIM	RCV000023564	SCV000044855	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2011-03-01	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000851197	SCV000993448	likely pathogenic	Combined oxidative phosphorylation deficiency	2017-05-25	no assertion criteria provided	research
Natera, Inc.	RCV000023564	SCV002081594	likely pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2021-01-28	no assertion criteria provided	clinical testing