Submissions for variant NM_024996.7(GFM1):c.749G>A (p.Arg250Gln)

dbSNP: rs752251570

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV001090179	SCV001244296	uncertain significance	Developmental regression; Relative macrocephaly; Severe muscular hypotonia	2020-04-08	criteria provided, single submitter	clinical testing	Homozygous or compound heterozygous variations in GFM1 gene (MIM*606639) are known to cause autosomal recessive combined oxidative phosphorylation deficiency 1 (COXPD1, MIM#609060). COXPD1 is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life [Smits et al., Eur J Hum Genet 2011]. The c.749G>A variant is not present in publicly available databases like 1000 Genomes and Exome Variant Server (EVS). It is present in Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a very low frequency, only in heterozygous state. The variant is not present in our in-house exome database. The variant was not reported to OMIM, Human Genome Mutation Database (HGMD) or ClinVar databases in any affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen-3, MutationTaster2, CADD etc. predicted this variant to be likely deleterious. However there are no documented functional studies to prove this. Due to lack of enough edicence and also considering the phenotype the variant has been classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002555936	SCV003457635	likely pathogenic	not provided	2024-07-10	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 250 of the GFM1 protein (p.Arg250Gln). This variant is present in population databases (rs752251570, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GFM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 870603). 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. This variant disrupts the p.Arg250 amino acid residue in GFM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21119709, 28216230). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526801	SCV005040245	uncertain significance	not specified	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: GFM1 c.749G>A (p.Arg250Gln) results in a conservative amino acid change located in the Translational (tr)-type GTP-binding domain (IPR000795) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.749G>A in individuals affected with Combined Oxidative Phosphorylation Deficiency 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 870603). A different missense affecting the same amino acid (p.Arg250Trp) is classified as pathogenic by our lab, and this might indicate the functional importance of the Arg250 residue. Based on the evidence outlined above, the variant was classified as uncertain significance.