Submissions for variant NM_017866.6(TMEM70):c.117_118dup (p.Ser40fs)

gnomAD frequency: 0.00003  dbSNP: rs796052056

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186214	SCV000239240	pathogenic	not provided	2017-03-20	criteria provided, single submitter	clinical testing	The c.117_118dupGT pathogenic variant in the TMEM70 gene has been reported previously in association with mitochondrial complex V deficiency an individual with psychomotor retardation, hypertrophic cardiomyopathy, lactic acidosis, methylglutaconic aciduria, and isolated deficiency of ATP synthase complex who was heterozygous for the c.117_118dupGT pathogenic variant and another pathogenic variant (Cízková et al., 2008). The c.117_118dupGT variant causes a frameshift starting with codon Serine 40, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ser40CysfsX11. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.117_118dupGT variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.117_118dupGT as a pathogenic variant.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678391	SCV000804460	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2017-03-23	criteria provided, single submitter	provider interpretation	This 15 year old female with severe intellectual disability was found to carry a paternally inherited variant in the TMEM70 gene. She also carries a maternally inherited variant (p.Gly47Glu) in this gene, which is currently classified as a variant of uncertain significance. Previous biochemical analyses do not suggest that this patient has a mitochondrial deficiency. The p.Ser40CysfsX11 variant has been reported previously in the compound heterozygous state in an affected individual. The p.Ser40CysfsX11 variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, a pathogenic variant in MEF2C was identified in this patient.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825576	SCV000966910	pathogenic	Mitochondrial proton-transporting ATP synthase complex deficiency	2018-08-10	criteria provided, single submitter	clinical testing	The p.Ser40CysfsX11 variant in TMEM70 has been previously reported in at least 3 compound heterozygous individuals with ATP synthase deficiency, all of which al so carried the pathogenic c.317-2A>G variant (Cizkova 2008, Cameron 2011, Magner 2015). This variant has also been reported in ClinVar (Variation ID 203989) and has been identified in 3/107484 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org). Functional studies provide some evidence that the p.Ser40CysfsX11 variant may impact protein function, by c ausing a reduction in ATP synthase activity (Cameron 2011). This variant is pred icted to cause a frameshift, which alters the protein?s amino acid sequence begi nning at position 40 and leads to a premature termination codon 11 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Biallelic loss of function of the TMEM70 gene has been associated with AT P synthase deficiency and related features, though this variant may be associate d with a milder phenotype after the neonate period (Honzik 2010, Magner 2015). I n summary, this variant meets criteria to be classified as pathogenic for isolat ed ATP synthase deficiency in an autosomal recessive manner. ACMG/AMP criteria a pplied: PVS1_Strong, PM3_Strong, PM2.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000678391	SCV001367478	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2020-03-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1_MOD,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000678391	SCV003269280	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2023-08-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser40Cysfs*11) in the TMEM70 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM70 are known to be pathogenic (PMID: 18953340, 21147908). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 203989). This premature translational stop signal has been observed in individual(s) with TMEM70-related conditions (PMID: 18953340). This variant is present in population databases (rs765909414, gnomAD 0.003%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000678391	SCV003801135	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2023-01-20	criteria provided, single submitter	clinical testing	Variant summary: TMEM70 c.117_118dupGT (p.Ser40CysfsX11) 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, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with ATP synthase deficiency in HGMD. The variant allele was found at a frequency of 4.8e-06 in 207742 control chromosomes. c.117_118dupGT has been reported in the literature in individuals affected with Complex V Deficiency, Nuclear Type 2 (Cizkov_2008, Cameron_2011, etc). At least one publication reports reduction in ATP synthase activity in fibroblasts from a patient who was compound heterozygous for the variant and another known loss-of-function variant (Cameron_2011). Four 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. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000678391	SCV000020720	pathogenic	Mitochondrial complex V (ATP synthase) deficiency nuclear type 2	2008-11-01	no assertion criteria provided	literature only