ClinVar Miner

Submissions for variant NM_015560.2(OPA1):c.1146A>G (p.Ile382Met) (rs143319805)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081747 SCV000113682 uncertain significance not provided 2014-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000081747 SCV000251994 likely pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The I382M variant in the OPA1 gene was originally reported in a single patient in association with autosomal dominant optic atrophy I (Schimpf et al., 2008). However, later this variant was shown to not be pathogenic alone, even when in the homozygous state (Bonifert et al., 2014). The I382M variant was reported as a phenotypic modifier when present in trans with an OPA1 pathogenic variant, leading to a phenotype of optic atrophy plus ataxia, ophthalmoplegia, peripheral neuropathy, muscle atrophy, ptosis, and spasticity (Schaaf et al., 2011; Bonifert et al., 2014). The I382M variant is observed in 28/30,780 alleles (0.09%) from individuals of South Asian background, and 166/276,896 global alleles (0.06%), in large population cohorts (Lek et al., 2016). Although the I382M variant is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret I382M as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000043607 SCV000442626 likely benign Dominant hereditary optic atrophy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Rare Disease Group, Clinical Genetics,Karolinska Institutet RCV000677258 SCV000681433 uncertain significance Optic nerve hypoplasia criteria provided, single submitter research
Invitae RCV000081747 SCV001035176 likely benign not provided 2018-07-11 criteria provided, single submitter clinical testing
Mendelics RCV000043607 SCV001136663 uncertain significance Dominant hereditary optic atrophy 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196157 SCV001366678 likely pathogenic Optic atrophy; Nystagmus; Nasal speech; Abnormality of the spinocerebellar tracts; Sensorimotor neuropathy; Abnormality of central motor function; Abnormality of central motor conduction; Spastic paraplegia 2019-06-10 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. This variant was detected in heterozygous state.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001249638 SCV001423605 uncertain significance Abortive cerebellar ataxia; Autosomal dominant optic atrophy plus syndrome; Dominant hereditary optic atrophy 2017-09-20 criteria provided, single submitter clinical testing [ACMG/AMP: PM1, PM3, PP1, PP3; BS3] This alteration is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1].
OMIM RCV000043607 SCV000071625 pathogenic Dominant hereditary optic atrophy 2011-08-01 no assertion criteria provided literature only
OMIM RCV000210748 SCV000266835 pathogenic Abortive cerebellar ataxia 2011-08-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000081747 SCV000802494 uncertain significance not provided 2017-08-18 no assertion criteria provided clinical testing

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