rs143319805

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:11

Conservation

PhyloP100: 0.888

Variant links:

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]

OPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000558 (85/152300) while in subpopulation AMR AF= 0.00131 (20/15302). AF 95% confidence interval is 0.000865. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3 link	c.1311A>G	p.Ile437Met	missense_variant	Exon 14 of 31	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 link	c.1311A>G	p.Ile437Met	missense_variant	Exon 14 of 31	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000622

AC:

156

AN:

250874

Hom.:

AF XY:

0.000715

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000249

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000785

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000899

AC:

1309

AN:

1455594

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

635

AN XY:

724588

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000715

GnomAD4 genome

AF:

0.000558

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000698

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000601

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000818

EpiControl

AF:

0.00107

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
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. -
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 -
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 -

not provided

Pathogenic:2Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	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, 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 25, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2014	- -
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	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2024	- -
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. -

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. -

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 atrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2019

- -

Optic nerve hypoplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.;.;D;D;.;.;.;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.37

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

.;.;.;H;H;.;.;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.8

D;D;D;.;D;D;.;.;.;.;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D;.;D;D;.;.;.;.;.

Sift4G

Uncertain

0.0020

D;D;D;.;D;D;.;.;.;.;.

Polyphen

1.0

D;.;.;D;D;.;.;.;.;.;.

Vest4

0.94

MVP

0.97

MPC

1.5

ClinPred

0.17

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over