rs80356529

chr3-193643996-G-Achr3-193643996-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_130837.3(OPA1):c.1499G>A(p.Arg500His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R500C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 9.97

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr3-193643995-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2683867.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 3-193643996-G-A is Pathogenic according to our data. Variant chr3-193643996-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193643996-G-A is described in Lovd as [Pathogenic]. Variant chr3-193643996-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.1499G>A	p.Arg500His	missense_variant	16/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.1499G>A	p.Arg500His	missense_variant	16/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000882 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	Published functional studies demonstrate a damaging effect (Del Dotto et al., 2018; Ban et al., 2010); 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: 25564500, 28841713, 20157015, 27696015, 32202296, 22800932, 16240368, 20185555, 14644237, 25641387, 18158317, 20952381, 28941528, 30293569, 31673222, 28494813, 29952689, 28378518, 28926202, 31609081, 19733158, 20385391, 12566046, 32025183, 33231680, 31500643) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 16, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 5091). This missense change has been observed in individual(s) with dominant optic atrophy (PMID: 18158317, 28926202, 31673222). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 445 of the OPA1 protein (p.Arg445His). -
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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	OPA1: PS2, PM2, PP1, PP3, PP4, PS3:Supporting -

Autosomal dominant optic atrophy classic form Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 27, 2023	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP1 supporting, PP3 supporting -

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

OPA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 01, 2023

Variant summary: OPA1 c.1334G>A (p.Arg445His) results in a non-conservative amino acid change located in the Dynamin, GTPase domain (IPR001401) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251254 control chromosomes (gnomAD). c.1334G>A has been reported in the literature in multiple individuals affected with dominant optic atrophy and this variant co-segregated with disease (Payne_2004, Leruez_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant reduced levels of GTP hydrolysis (Ban_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20185555, 24798923, 15531309). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Apr 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D;D;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.;.;.;.
Vest4		0.89
MutPred		0.67		.;.;Gain of glycosylation at S501 (P = 0.164);.;.;.;.;.;.;.;.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs80356529; hg19: chr3-193361785;