Submissions for variant NM_032380.5(GFM2):c.569G>A (p.Arg190Gln)

gnomAD frequency: 0.00003  dbSNP: rs761283105

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197518	SCV000251573	likely pathogenic	not provided	2014-07-24	criteria provided, single submitter	clinical testing	p.Arg190Gln (CGA>CAA): c.569 G>A in exon 8 of the GFM2 gene (NM_032380.3). The R190Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the R190Q variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in LSME-MITOP panel(s).
Invitae	RCV000197518	SCV002239858	uncertain significance	not provided	2023-12-11	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 190 of the GFM2 protein (p.Arg190Gln). This variant is present in population databases (rs761283105, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive mitochondrial disease (PMID: 29075935). ClinVar contains an entry for this variant (Variation ID: 214509). 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 GFM2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000197518	SCV004042224	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	GFM2: PM2, PM3
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000515487	SCV000605919	pathogenic	Mitochondrial disease	2017-09-15	no assertion criteria provided	clinical testing
OMIM	RCV000767875	SCV000898488	pathogenic	Combined oxidative phosphorylation deficiency 39	2019-04-19	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV001824674	SCV002075229	not provided	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1; Combined oxidative phosphorylation deficiency 39		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 08-12-2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.