Submissions for variant NM_130837.3(OPA1):c.113_130del (p.Arg38_Ser43del)

dbSNP: rs863224140

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487644	SCV000252008	likely benign	not provided	2021-01-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22857269, 19303950, 12036970, 11810270, 27890673, 31521625, 20157015, 32420686, 31500643)
Eurofins Ntd Llc (ga)	RCV000487644	SCV000331095	uncertain significance	not provided	2016-02-12	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415438	SCV000492829	uncertain significance	Elevated circulating creatine kinase concentration; Muscle weakness; Ptosis; Hypomimic face; Hepatic steatosis; EMG abnormality; EMG: myopathic abnormalities; EMG: myotonic runs; Progressive proximal muscle weakness	2015-04-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487644	SCV000575383	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	OPA1: BS1
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000489905	SCV000575933	uncertain significance	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	2017-04-25	criteria provided, single submitter	clinical testing	This variant has been identified at an allele frequency of 0.22% in both ExAC overall and in European Americans in ESP; three homozygous individuals have been identified in these databases combined. However, this condition exhibits marked variable expressivity and incomplete penetrance, and compound heterozygous individuals have been reported with milder pathogenic variants. A previously reported patient (Milone, 2009) had a similar presentation to the patient observed in our clinic, but family segregation studies were not done in that case. The patient tested in our clinic presented with fatigue, ataxia, muscle weakness, peripheral neuropathy, ptosis, and external ophthalmoplegia. She did not have optic atrophy at age 51. Her mother had a similar clinical presentation and was deceased. The patient is also an FMR1 premutation carrier. This OPA1 variant was inherited from her father, who at age 74, had no clinical symptoms of neurological or mitochondrial dysfunction, although he had a history of migraines.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000487644	SCV000610798	uncertain significance	not provided	2017-04-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000197686	SCV000614370	benign	not specified	2017-07-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487644	SCV001117421	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197504	SCV001368272	uncertain significance	Abortive cerebellar ataxia	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000197686	SCV004241859	likely benign	not specified	2023-12-05	criteria provided, single submitter	clinical testing	Variant summary: OPA1 c.113_130del18 (p.Arg38_Ser43del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0022 in 1613980 control chromosomes in the gnomAD database, including 10 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although are not suggestive of a variant associated with highly penetrant autosomal dominant or recessive disease. c.113_130del18 has been reported in the literature in individuals affected with OPA1-Related Disorders (e.g., Thiselton_2002, Milone_2009, Barboni_2013, vandeWarrenburg_2016, Tingaud-Sequeira_2017, Heighton_2019, Marcos_2020, Rots_2023), although the variant was also found in healthy homozygous and heterozygous controls (e.g., vandeWarrenburg_2016) and found not to segregate with disease in several families (e.g., Tingaud-Sequeira_2017, Marcos_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12036970, 19303950, 23388408, 27165006, 27890673, 31521625, 32420686, 37196654). Nine submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign/likely benign, n = 3; VUS, n = 6). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004737308	SCV005352207	likely benign	OPA1-related disorder	2024-06-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).