rs121908375

Positions:

chr3-193637280-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_130837.3(OPA1):c.1034G>A(p.Arg345Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OPA1
NM_130837.3 missense, splice_region

Scores

Splicing: ADA: 0.9277

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.98

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:

OPA1 (HGNC:):

OPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-193637280-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant 3-193637280-G-A is Pathogenic according to our data. Variant chr3-193637280-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193637280-G-A is described in Lovd as [Pathogenic]. Variant chr3-193637280-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-193637280-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3 linkuse as main transcript	c.1034G>A	p.Arg345Gln	missense_variant, splice_region_variant	10/31	ENST00000361510.8	NP_570850.2	O60313-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8 linkuse as main transcript	c.1034G>A	p.Arg345Gln	missense_variant, splice_region_variant	10/31	5	NM_130837.3	ENSP00000355324.2		O60313-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	Functional studies support a deleterious effect on mitochondrial morphology and cellular reactive oxygen species level (Zhang et al., 2016; Olichon et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33300680, 27858935, 30293569, 22779427, 21745197, 23916084, 25564500, 11017080, 17167772, 26867657, 32025183) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 290 of the OPA1 protein (p.Arg290Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant optic atrophy (PMID: 11017080, 11440988, 11810270, 22779427, 25564500). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg345Gln. ClinVar contains an entry for this variant (Variation ID: 5084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects OPA1 function (PMID: 17167772, 26867657). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 19, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study in mouse embryonic fibroblasts showed this variant caused significant decrease of mtDNA content and completely fragmented the mitochondrial network (PMID: 30293569). The variant is located in a region that is considered important for protein function and/or structure. -

Autosomal dominant optic atrophy classic form

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PS3, PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 18, 2018

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple affected families [PMID 11017080, 22779427, 25564500, 21745197] Clinical variability has been previously reported and may be due to incomplete penetrance; some carriers can be unaffected [PMID 17724190, 12488262] -

Retinal dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jan 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;.;.;D;D;.;.;.;.;.;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.35

.;.;.;N;N;.;.;.;.;.;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.87

Sift

Benign

0.037

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.85

MutPred

0.75

.;.;Loss of sheet (P = 0.0817);.;.;.;.;.;.;.;.;

MVP

0.96

MPC

1.5

ClinPred

0.99

GERP RS

5.3

Varity_R

0.46

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.58

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

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