rs121908375

Positions:

• chr3-193637280-G-A

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.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. R345W) has been classified as Likely 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:9
• Conservation: PhyloP100: 9.98

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr3-193637279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402217.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
OPA1	NM_130837.3	c.1034G>A	p.Arg345Gln	missense_variant, splice_region_variant	10/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.1034G>A	p.Arg345Gln	missense_variant, splice_region_variant	10/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448660 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 721338

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Autosomal dominant optic atrophy classic form Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 21, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
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 -

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] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
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	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.35	.;.;.;N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.79	T
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	D
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

Other links and lift over

dbSNP: rs121908375; hg19: chr3-193355069;