chr19-45553741-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_025136.4(OPA3):c.313C>G(p.Gln105Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q105K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

OPA3
NM_025136.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 2.89

Publications

12 publications found

Variant links:

Genes affected

OPA3 (HGNC:8142): (outer mitochondrial membrane lipid metabolism regulator OPA3) The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

OPA3 Gene-Disease associations (from GenCC):

optic atrophy 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
3-methylglutaconic aciduria type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae)

OPA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

PP5

Variant 19-45553741-G-C is Pathogenic according to our data. Variant chr19-45553741-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
OPA3	NM_025136.4 link	c.313C>G	p.Gln105Glu	missense_variant	Exon 2 of 2	ENST00000263275.5	NP_079412.1
OPA3	XM_006723403.5 link	c.154C>G	p.Gln52Glu	missense_variant	Exon 3 of 3		XP_006723466.1
OPA3	NM_001017989.3 link	c.143-24285C>G		intron_variant	Intron 1 of 1		NP_001017989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OPA3	ENST00000263275.5 link	c.313C>G	p.Gln105Glu	missense_variant	Exon 2 of 2	1	NM_025136.4	ENSP00000263275.4
OPA3	ENST00000323060.4 link	c.143-24285C>G		intron_variant	Intron 1 of 1	1		ENSP00000319817.3
OPA3	ENST00000544371.1 link	c.154C>G	p.Gln52Glu	missense_variant	Exon 2 of 2	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726012

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111680

Other (OTH)

AF:

0.00

AC:

AN:

60310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Optic atrophy 3

Pathogenic:3Other:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with 3-methylglutaconic aciduria, type III (MIM#258501) (PMID: 31928268). The precise mechanism for missense is unknown, however it was suggested they could cause dominant Optic atrophy 3 with cataract (MIM#165300) through either dominant negative or gain of function mechanism (PMID: 31119193). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and interfamilial variability are reported (PMID: 25159689). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated coiled-coil domain (Uniprot). (I) 0701 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A different variant in the same codon resulting in a change to an arginine has been reported as VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most frequent mutation reported in patients with dominant optical atrophy (ClinVar, PMID: 25159689, 31119193). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 07, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Dec 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported heterozygous in multiple individuals with optic atrophy and cataracts, with some individuals also reported to have hearing loss, gastrointestinal symptoms, and/or symptoms of peripheral neuropathy (PMID: 25159689, 15342707, 22797356, 24136862, 31119193); Segregates with disease in many affected individuals from several families in published literature (PMID: 24136862, 15342707, 22797356, 25159689); In silico analysis suggests that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15342707, 18496845, 24749080, 22797356, 31119193, 39166438, 24136862, 25159689) -

3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3

Pathogenic:1

Jan 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 4241). This missense change has been observed in individuals with autosomal dominant optic atrophy and cataract (PMID: 15342707, 24136862, 25159689). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 105 of the OPA3 protein (p.Gln105Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

0.0069

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.085

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.6

L;.

PhyloP100

2.9

PROVEAN

Benign

-0.90

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.16

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.32

B;.

Vest4

0.36

MutPred

0.74

Loss of MoRF binding (P = 0.0769);.;

MVP

0.77

ClinPred

0.39

GERP RS

3.7

Varity_R

0.34

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over