rs143319805
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_130837.3(OPA1):c.1311A>G(p.Ile437Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,607,894 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 3 hom. )
Consequence
OPA1
NM_130837.3 missense
NM_130837.3 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 0.888
Genes affected
OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a domain Dynamin-type G (size 276) in uniprot entity OPA1_HUMAN there are 128 pathogenic changes around while only 5 benign (96%) in NM_130837.3
BP4
Computational evidence support a benign effect (MetaRNN=0.37358683).
BS2
High Homozygotes in GnomAdExome4 at 3 SD gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| OPA1 | NM_130837.3 | c.1311A>G | p.Ile437Met | missense_variant | 14/31 | ENST00000361510.8 | NP_570850.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| OPA1 | ENST00000361510.8 | c.1311A>G | p.Ile437Met | missense_variant | 14/31 | 5 | NM_130837.3 | ENSP00000355324.2 |
Frequencies
GnomAD3 genomes 0.000565 AC: 86AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000622 AC: 156AN: 250874Hom.: 0 AF XY: 0.000715 AC XY: 97AN XY: 135754
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GnomAD4 exome AF: 0.000899 AC: 1309AN: 1455594Hom.: 3 Cov.: 30 AF XY: 0.000876 AC XY: 635AN XY: 724588
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GnomAD4 genome 0.000558 AC: 85AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Abortive cerebellar ataxia Pathogenic:4Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 10, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP3,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.1311A>G p.Ile437Met variant in OPA1 gene has been reported in heterozygous as well as compound heterozygous state in individuals (Schaaf CP et al). Experimental studies have shown a damaging effect (Alessia Nasca et al,2017). This variant is reported with the allele frequency 0.05% in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Likely Pathogenic/Pathogenic/Uncertain Significance/Likely Benign. The amino acid Ile at position 437 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile437Met in OPA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 05, 2023 | ACMG classification criteria: PM3 very strong, PP1 supporting, PP3 supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Biallelic variants are associated with early-onset Behr syndrome, whereas heterozygous pathogenic variants have been associated with optic atrophy with or without syndrome (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 30165240). (N) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to methionine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (166 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools, highly conserved with a minor amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (GTPase; PMID: 24970096). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting (ClinVar). The variant seems to act as a hypomorphic allele rather than causative, resulting in a more severe phenotype, such as optic atrophy plus syndrome or Behr syndrome when in trans with truncating variants (PMID: 21636302, PMID: 24970096, PMID: 25146916, PMID: 30972688, PMID: 17722006). (N) 1002 - Moderate functional evidence show mildly abnormal protein function (PMID: 25146916, PMID: 24970096, PMID: 30293569) (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
not provided Pathogenic:2Uncertain:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 382 of the OPA1 protein (p.Ile382Met). This variant is present in population databases (rs143319805, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Behr syndrome and/or optic atrophy plus, Behr syndrome, optic neuropathy (PMID: 21636302, 24970096, 25012220, 25146916, 28494813, 30972688, 33841295, 35741767). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The effect of this variant on homozygous individuals has not been well documented in the literature (PMID: 24970096). Heterozygous individuals may either have mild disease symptoms or be unaffected (PMID:18496845, 19319978, 25012220, 27290639, 32040484). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1311A>G/p.I437M. ClinVar contains an entry for this variant (Variation ID: 50866). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OPA1 protein function with a positive predictive value of 80%. Studies have shown that this missense change alters OPA1 gene expression (PMID: 24970096, 30293569). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2024 | Variant is not considered to be pathogenic when present alone, even in the homozygous state (PMID: 27696015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30293569, 27290639, 31782039, 32371413, 32202296, 21636302, 24970096, 25146916, 17722006, 25012220, 28378518, 30972688, 34426522, 34242285, 32040484, 33841295, 31816670, 34732400, 26455272, 28494813, 35741767, 11440988, 27696015) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 15, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 25, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 20, 2023 | PP3 - |
Autosomal dominant optic atrophy classic form Pathogenic:1Uncertain:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
OPA1-related disorder Pathogenic:1Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 12, 2023 | The OPA1 c.1311A>G variant is predicted to result in the amino acid substitution p.Ile437Met. This variant (also known as c.1146A>G [p.Ile382Met] in transcript NM_015560.2) has been reported in the heterozygous state in patients with autosomal dominant optic atrophy (Schimpf et al. 2008. PubMed ID: 17722006; Ferré et al. 2009. PubMed ID: 19319978; Carelli et al. 2015. PubMed ID: 25146916). However, other individuals who carried this variant in the heterozygous or even homozygous states were reportedly asymptomatic (Bonifert et al. 2014. PubMed ID: 24970096; Bonneau et al. 2014. PubMed ID: 25012220; Carelli et al. 2015. PubMed ID: 25146916). Several reports indicate that this variant may possibly be a mild pathogenic variant that contributes to increased severity of disease when present in the compound heterozygous state with a known pathogenic variant (Bonifert et al. 2014. PubMed ID: 24970096; Bonneau et al. 2014. PubMed ID: 25012220; Nasca et al. 2017. PubMed ID: 28494813). This variant has been classified as likely benign, uncertain, likely pathogenic, and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/50866). This variant is reported in 0.098% of alleles in individuals of South Asian descent in gnomAD, including >150 heterozygotes in the entire gnomAD population database. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 17, 2024 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2020 | The c.1146A>G (p.I382M) alteration is located in exon 12 (coding exon 12) of the OPA1 gene. This alteration results from an A to G substitution at nucleotide position 1146, causing the isoleucine (I) at amino acid position 382 to be replaced by a methionine (M). Based on the available evidence, the OPA1 c.1146A>G (p.I382M) alteration is classified as pathogenic for autosomal recessive Behr syndrome; however, it is unlikely to be causative of autosomal dominant OPA1-related optic atrophy or autosomal dominant OPA1-related optic atrophy plus syndrome. Based on data from gnomAD, the G allele has an overall frequency of 0.06% (166/282274) total alleles studied. The highest observed frequency was 0.1% (30/30614) of South Asian alleles. This alteration has been described in trans with a pathogenic alteration in multiple families presenting with early-onset optic atrophy and variable additional abnormalities which can include neuropathy, ataxia, spasticity, hypotonia, dysphagia, gastrointestinal dysmotility, and neurodevelopmental delay. The c.1146A>G (p.I382M) alteration alone is not observed to be disease-causing in either the homozygous or heterozygous state, but has clinical implications when occurring in trans with another pathogenic allele (Bonifert, 2014; Nasca, 2017; Schaaf, 2011). This alteration is also reported as p.I437M in the literature. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2024 | Variant summary: OPA1 c.1146A>G (p.Ile382Met) results in a conservative amino acid change located in the Dynamin GTPase domain (IPR001401) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 1607894 control chromosomes in the gnomAD database, including 3 homozygotes. c.1146A>G (also known as c.1311A>G/p.I437M) has been reported in the literature in multiple compound heterozygous individuals affected with Behr syndrome and/or optic atrophy (examples: Schaaf_2011, Bonifert_2014, Bonneau_2014, Nasca_2017, Carelli_2015, Zerem_2019, Othman_2022). In these studies, c.1146A>G variant was inherited from an asymptomatic parent, and at-least one parent was homozygous for this variant (Bonifert_ 2014). It has also been reported in heterozygous state in individuals affected with mitochondrial disorder (Pronicka_2016) and inherited optic neuropathy (Charif_ 2021) without strong evidence for causality. At least one publication reports experimental evidence using a yeast complementation assay that this variant has a very mild growth defect only at dilute concentrations (example: Nasca_2017). Taken together, these results suggest c.1146A>G pathogenic effect is dependent on the presence of a second pathogenic allele in trans. ClinVar contains an entry for this variant (Variation ID: 50866). The following publications have been ascertained in the context of this evaluation (PMID: 28494813, 24970096, 21636302, 25012220 , 25146916, 33841295, 30972688, 27290639, 31816670, 35741767). Based on the evidence outlined above, the variant was classified as uncertain significance for Autosomal Dominant OPA1-Related Disorders. - |
Optic atrophy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2019 | - - |
Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Sep 20, 2017 | [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]. - |
Optic nerve hypoplasia Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Rare Disease Group, Clinical Genetics, Karolinska Institutet | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;D;D;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;H;H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;D;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.;D;D;.;.;.;.;.
Sift4G
Uncertain
D;D;D;.;D;D;.;.;.;.;.
Polyphen
D;.;.;D;D;.;.;.;.;.;.
Vest4
MVP
MPC
1.5
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at