Submissions for variant NM_017866.6(TMEM70):c.317-2A>G

gnomAD frequency: 0.00011  dbSNP: rs183973249

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000390940	SCV000329823	pathogenic	not provided	2021-03-25	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; cDNA analysis found that c.317-2A>G leads to abnormal splicing and loss of normal TMEM70 transcript (Cizkova et al. 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29678161, 30096161, 24485043, 27649480, 31729175, 20335238, 18953340, 21815885, 22433607, 26550569, 29502919, 31589614)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000390940	SCV000610483	pathogenic	not provided	2017-05-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000000570	SCV000680409	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2017-11-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000000570	SCV000915260	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2018-08-22	criteria provided, single submitter	clinical testing	The TMEM70 c.317-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product.Across a selection of available literature, the c.317-2A>G variant has been reported in a homozygous state in 36 probands with mitochondrial complex V (ATP Synthase) deficiency, nuclear type (Cizkova et al. 2008; Tort et al. 2011; Braczynski et al. 2015). Cizkova et al. (2008) further demonstrated segregation of the c.317-2A>G variant in six families, in which all the affected individuals were homozygous, all parents were heterozygous, and unaffected siblings were either wild type or heterozygous for the variant. The c.317-2A>G variant was absent from 101 controls and is reported at a frequency of 0.00035 in the Latino population of the Exome Aggregation Consortium. The c.317-2A>G variant occurs at a canonical splice site and has been shown to result in aberrant splicing and loss of the transcript (Cizkova et al. 2008; Hejzlarova et al. 2011). Functional studies using fibroblasts from probands harboring the c.317-2A>G variant showed a significant deficiency in ATP synthase compared with control cells, and ultrastructural analysis revealed defects in mitochondrial morphology (Havlíčková Karbanová et al. 2012; Braczynski et al. 2015). Based on the collective evidence, the c.317-2A>G variant is classified as pathogenic for mitochondrial complex V (ATP Synthase) deficiency, nuclear type. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000390940	SCV001249595	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000570	SCV001367701	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2018-11-22	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5.
Invitae	RCV000000570	SCV001374009	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the TMEM70 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs183973249, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with mitochondrial complex V (ATP synthase) deficiency (PMID: 18953340, 26550569). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 540). Studies have shown that disruption of this splice site alters TMEM70 gene expression (PMID: 1895334). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000390940	SCV001447095	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000000570	SCV002012492	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2021-07-27	criteria provided, single submitter	research	ACMG codes: PVS1; PS3; PS4; PM2; PP1; PP5
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000000570	SCV002574817	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2022-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000000570	SCV002811690	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2022-02-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000390940	SCV002817231	pathogenic	not provided	2020-06-05	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been detected homozygous or compound heterozygous in multiple individuals with clinical features consistent with this disorder (PMID: 26550569, 24485043, 21815885, 18953340, and 20335238). This variant segregates with disease in multiple families (PMID: 26550569, 24485043, and 18953340). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22433607, 20937241, and 18953340).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000570	SCV003801136	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: TMEM70 c.317-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Cizkova_2008). The variant allele was found at a frequency of 7.2e-05 in 250692 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TMEM70 causing Complex V Deficiency, Nuclear Type 2 (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.317-2A>G has been reported in the literature in multiple individuals affected with Complex V Deficiency, Nuclear Type 2 with co-segregation data providing strong evidence for causality (e.g., Cizkova_2008, Cameron_2011, Braczynski_2015, Torraco_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, showing the variant results in a strong reduction in ATP synthesis activity (ranging from 40% to 95% reduction in activity depending on patient and type of tissue) (Cizkova_2008, Cameron_2011, Torraco_2012, Havlickova-Karbanova_2012, Braczynski_2015) as well as a complete absense of TMEM70 protein (Hejzlarova_2011, Torraco_2012) or mRNA (Torraco_2012) in patient fibroblasts. 12 ClinVar submitters (evaluation after 2014) have cited this variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV003128385	SCV003804841	likely pathogenic	See cases	2022-09-30	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2
Revvity Omics, Revvity	RCV000000570	SCV003820358	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2023-01-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000570	SCV003834906	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2021-02-25	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000390940	SCV004026105	pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP, PVS1_STR
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000000570	SCV004032459	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2023-03-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV003389034	SCV004101236	pathogenic	Neurodevelopmental disorder	2023-03-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415606	SCV004113915	pathogenic	TMEM70-related disorder	2023-04-28	criteria provided, single submitter	clinical testing	The TMEM70 c.317-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be pathogenic in patients with neonatal mitochondrial encephalocardiomyopathy (Cízková et al. 2008. PubMed ID: 18953340; Honzík et al. 2010. PubMed ID: 20335238). Functional studies showed this variant leads to absence of the TMEM70 protein and reduction in functional ATP synthase to less than 30% of control values (Havlíčková Karbanová et al. 2012. PubMed ID: 22433607). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-74893388-A-G). Variants that disrupt the consensus splice acceptor site in TMEM70 are expected to be pathogenic. This variant is interpreted as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000000570	SCV005042731	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2		criteria provided, single submitter	clinical testing
OMIM	RCV000000570	SCV000020719	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2014-03-01	no assertion criteria provided	literature only