Submissions for variant NM_024996.7(GFM1):c.2011C>T (p.Arg671Cys)

gnomAD frequency: 0.00006  dbSNP: rs201408725

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197077	SCV000251564	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate oxidative phosphorylation dysfunction in liver mitochondria (Molina-Berenguer et al., 2022); 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: 27345796, 21986555, 22277967, 25852744, 26937387, 32313153, 31680380, 34919756, 34440436, 35581596)
Fulgent Genetics, Fulgent Genetics	RCV000763507	SCV000894303	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2018-10-31	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades	RCV000763507	SCV001160692	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1		criteria provided, single submitter	clinical testing
Invitae	RCV000197077	SCV001236979	pathogenic	not provided	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the GFM1 protein (p.Arg671Cys). This variant is present in population databases (rs201408725, gnomAD 0.03%). This missense change has been observed in individual(s) with oxidative phosphorylation deficiency (PMID: 21986555, 22277967, 25852744, 31680380). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214500). 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 GFM1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Kids Research, The Children's Hospital at Westmead	RCV000763507	SCV001244724	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000763507	SCV002024241	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2022-06-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000763507	SCV004047783	likely pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1		criteria provided, single submitter	clinical testing	The missense c.2011C>T(p.Arg671Cys) variant in GFM1 gene has been reported previously in the homozygous and compound heterozygous state in patients with complex IV deficiency (Galmiche et al., 2012; Calvo et al., 2012). This variant is reported with the allele frequency 0.006% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Arg at position 671 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg671Cys in GFM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, the variant has been classified as Likely pathogenic.
Baylor Genetics	RCV000763507	SCV004199302	pathogenic	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	2023-09-22	criteria provided, single submitter	clinical testing