rs80356530

Positions:

• chr3-193667167-CAGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_130837.3(OPA1):​c.2873_2876del​(p.Val958GlyfsTer3) variant causes a splice acceptor, coding sequence 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: OPA1 NM_130837.3 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.036089238 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.8, offset of 0 (no position change), new splice context is: ttttaactttctttaaacAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.2873_2876del	p.Val958GlyfsTer3	splice_acceptor_variant, coding_sequence_variant	29/31	ENST00000361510.8	NP_570850.2
LOC102724808	XR_924835.3	n.420+1749_420+1752del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.2873_2876del	p.Val958GlyfsTer3	splice_acceptor_variant, coding_sequence_variant	29/31	5	NM_130837.3	ENSP00000355324	A1

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:29 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2022	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) This variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2022	PP1, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -

Autosomal dominant optic atrophy classic form Pathogenic:9 Other:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 18, 2017	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. -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 17, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 20, 2023	Criteria applied: PVS1,PS4,PS3_MOD -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 26, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 18, 2020	- -

OPA1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 31, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Apr 07, 2017

- -

Abortive cerebellar ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Mar 06, 2023

ACMG categories: PVS1,PP1,PP4,PP5 -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

Nov 23, 2022

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. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 12, 2017

- -

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;