Submissions for variant NM_152269.5(MTRFR):c.210del (p.Gly72fs)

gnomAD frequency: 0.00016  dbSNP: rs576462794

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200775	SCV000251229	pathogenic	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 95 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 20598281, 24284555, 27858754, 30609409, 36344503)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000000071	SCV000731312	pathogenic	Combined oxidative phosphorylation defect type 7	2016-12-19	criteria provided, single submitter	clinical testing	The p.Gly72AlafsX13 variant in C12orf65 has been reported in 2 homozygous and 1 compound heterozygous probands with clinical features of combined oxidative phos phorylation deficiency type 7 (COXPD7) and segregated with disease in one additi onal affected sibling (Antonika 2010, Heidary 2013, Wesolowska 2015). This varia nt has also been identified in 1/8254 of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs57646274). This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 72 and leads to a premature termination codon 1 3 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Biallelic loss of function of the C12orf65 gene has been a ssociated with COXPD7. In summary, this variant meets criteria to be classified as pathogenic for COXPD7 in an autosomal recessive manner based upon its occurr ence in affected individuals and predicted functional impact.
Mayo Clinic Laboratories, Mayo Clinic	RCV000200775	SCV000802804	pathogenic	not provided	2021-12-17	criteria provided, single submitter	clinical testing	PP1, PM2, PM3, PVS1
Illumina Laboratory Services, Illumina	RCV000000071	SCV000915580	likely pathogenic	Combined oxidative phosphorylation defect type 7	2018-08-23	criteria provided, single submitter	clinical testing	The C12orf65 c.210delA (p.Gly72AlafsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly72AlafsTer13 variant has been reported in three studies and is found in four probands with combined oxidative phosphorylation deficiency (COXPD) including in two in a homozygous state and in two siblings in a compound heterozygous state (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00032 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly72AlafsTer13 variant resulted in reduced complex IV activity and reduced quantities of complex I, IV, and V in proband fibroblasts (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Based on the potential impact of frameshift variants and available evidence, the p.Gly72AlafsTer13 variant is classified as pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000200775	SCV001502153	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	MTRFR: PVS1, PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382822	SCV001581757	pathogenic	Combined oxidative phosphorylation defect type 7; Spastic paraplegia	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly72Alafs*13) in the C12orf65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the C12orf65 protein. This variant is present in population databases (rs576462794, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of C12orf65-related conditions (PMID: 20598281, 24284555, 27858754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000200775	SCV002018008	pathogenic	not provided	2020-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000071	SCV002600594	pathogenic	Combined oxidative phosphorylation defect type 7	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. One study of C12orf65 mRNA from a homozygous patient showed the level of the C12orf65 mRNA was not significantly reduced, suggesting that nonsense-mediated mRNA decay does not contribute to the loss of function of the C12orf65 gene product (Antonicka_2010). Truncations downstream of this position have been reported with various Mitochondrial disorders in HGMD. The variant allele was found at a frequency of 0.00018 in 251348 control chromosomes. c.210delA has been reported in the literature in multiple individuals affected mitochondrial disorders including Leigh syndrome, optic atrophy, and ophthalmoplegia (examples: Antonicka_2010, Heidary_2014, Wesolowska_2015, Schon_2021). These data indicate that the variant is very likely to be associated with disease. Seven 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.
OMIM	RCV000000071	SCV000020214	pathogenic	Combined oxidative phosphorylation defect type 7	2010-07-09	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000200775	SCV001741202	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000200775	SCV001975716	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000000071	SCV002818348	not provided	Combined oxidative phosphorylation defect type 7		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 10-10-2014 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.