rs80356530

Variant names:

• chr3-193667167-CAGTT-C
• rs80356530
• NM_130837.3:c.2873_2876delTTAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000361510.8(OPA1):​c.2873-2_2874delAGTT​(p.Val958fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,453,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V958V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: OPA1 ENST00000361510.8 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:2
• Conservation: PhyloP100: 9.95

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]

LOC102724808 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-193667167-CAGTT-C is Pathogenic according to our data. Variant chr3-193667167-CAGTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193667167-CAGTT-C is described in Lovd as [Pathogenic]. Variant chr3-193667167-CAGTT-C is described in Lovd as [Likely_pathogenic]. Variant chr3-193667167-CAGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.2873_2876delTTAG	p.Val958fs	frameshift_variant, splice_region_variant	Exon 29 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.2873-2_2874delAGTT	p.Val958fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 29 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251242 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135822

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 32 AN: 1301222 Hom.: 0 AF XY: 0.0000229 AC XY: 15 AN XY: 656424

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000259

Gnomad4 OTH exome AF: 0.0000182

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74256

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant optic atrophy classic form Pathogenic:10 Other:2

Jun 20, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PS3_MOD -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant was identified in multiple participants. Variant interpreted as Pathogenic and reported, most recently, on 11-07-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 20417570, 14961560). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 18, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 18, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant (deletion of four nucleotides) in the OPA1 gene was identified in a male young patient and also his mother, both diagnosed with optic atrophy 1. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 17, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

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 OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants clustered within the GTPase domain generally develop optic atrophy plus syndrome. Lastly, biallelic variants have been associated with early-onset Behr syndrome (PMIDs: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). In addition, this variant has been specifically reported to have a penetrance ranging from 43-62% (PMID: 11440989). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 (15 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical diagnostic laboratories (ClinVar) and is regarded as a pathogenic variant in GeneReviews. While this variant has primarily been reported in individuals with autosomal dominant optic atropy, it has also been reported as compound heterozygous in two siblings with Behr syndrome. The father of the siblings, who is heterozygous for the variant, was diagnosed with mild optic atrophy and bilateral sensorineural hearing loss (PMID: 21636302, OMIM). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Skin fibroblasts from affected individuals heterozygous for this variant demonstrated reduced OPA1 protein levels and abnormal mitochondrial morphology and fusion compared to control fibroblasts (PMID: 18222991). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:10

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OPA1: PVS1, PM2, PS4:Moderate -

May 03, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant is one of the most common pathogenic variants associated with autosomal dominant optic atrophy (ADOA; PMID: 11440989, 22857269) and therefore the frequency of this variant in the general population is consistent with pathogenicity ((Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been reported to exhibit reduced penetrance (PMID: 11440989). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18222991) -

Aug 27, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM2_moderate, PS4, PVS1 -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val903Glyfs*3) in the OPA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OPA1 are known to be pathogenic (PMID: 11440988, 20157015, 20952381, 25012220). This variant is present in population databases (rs745560444, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dominant optic atrophy (PMID: 11017079, 26385429). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2708delTTAG and c.2873_2876delTTAG (p.V958Gfs*3). ClinVar contains an entry for this variant (Variation ID: 5082). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An Opa1 mouse model carrying the c.2708_2711delTTAG variant displayed a multi-systemic poly-degenerative phenotype including signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia, cardiomyopathy, and premature age-related axonal and myelin degenerations (Sarzi et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23665194, 25012220, 26031781, 21646330, 25699009, 26385429, 27260406, 25564500, 23250881, 27974645, 11017079, 28848318, 15505825, 20952381, 11440989, 32025183, 31500643, 31589614, 33300680) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OPA1-related disorder Pathogenic:2

Mar 18, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OPA1 c.2708_2711delTTAG (p.Val903GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251242 control chromosomes (gnomAD). c.2708_2711delTTAG has been reported in the literature in multiple individuals affected with autosomal dominant optic atrophy (Cohn_2008). 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 showed it was more prone to cell death than controls after an exogenous oxidative stress in fibroblasts (Zanna_2008). The following publications have been ascertained in the context of this evaluation (PMID: 17306754, 18222991). ClinVar contains an entry for this variant (Variation ID: 5082). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OPA1 c.2873_2876delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Val958Glyfs*3). This variant is also often denoted as c.2708_2711delTTAG (p.Val903Glyfs*3) in the alternate transcript NM_015560.2. This variant has been reported many times as causative for autosomal dominant optic atrophy (see for examples Delettre et al. 2000. PubMed ID: 11017079; Pretegiani et al. 2011. PubMed ID: 21646330; Gaier et al. 2017. PubMed ID: 28848318; Lin et al. 2021. PubMed ID: 34573359). This variant has also been reported in the compound heterozygous state in an individual with early-onset Behr syndrome and the unaffected mother was a carrier of this variant, suggesting there may be incomplete penetrance (Bonneau et al. 2014. PubMed ID: 25012220). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-193384956-CAGTT-C). Frameshift variants in OPA1 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5082). Given all the evidence, we interpret c.2873_2876del (p.Val958Glyfs*3) as pathogenic. -

Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C1847730:Glaucoma, normal tension, susceptibility to;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;C4225163:Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Pathogenic:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Apr 07, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Optic atrophy Pathogenic:1

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Mar 06, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PP1,PP4,PP5 -

Abortive cerebellar ataxia Pathogenic:1

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait Pathogenic:1

Nov 23, 2022

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

3-Methylglutaconic aciduria type 3 Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PM3_Strong, PS3, PM2 -

Retinal dystrophy Pathogenic:1

Oct 12, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 7
DS_AL_spliceai		0.98		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356530; hg19: chr3-193384956;