rs143319805

Variant names:

• chr3-193643378-A-G
• rs143319805
• NM_130837.3:c.1311A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4 BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:11
• 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]

ACMG classification

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	c.1311A>G	p.Ile437Met	missense_variant	Exon 14 of 31	ENST00000361510.8	NP_570850.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152182 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000715 AC XY: 97 AN XY: 135754

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.: 3 Cov.: 30 AF XY: 0.000876 AC XY: 635 AN XY: 724588

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: 85 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74484

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.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Abortive cerebellar ataxia Pathogenic:4 Uncertain:1

Jun 10, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP3,PP5. -

Apr 05, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM3 very strong, PP1 supporting, PP3 supporting -

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2 Uncertain:3

Feb 15, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 25, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Autosomal dominant optic atrophy classic form Pathogenic:1 Uncertain:2

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 21, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OPA1-related disorder Pathogenic:1 Uncertain:1

Dec 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jan 17, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 16, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2019

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Uncertain:1

Sep 20, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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]. -

Optic nerve hypoplasia Uncertain:1

-

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	23
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	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	.;.;.;H;H;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
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	T
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

Other links and lift over

dbSNP: rs143319805; hg19: chr3-193361167;