NM_130837.3(OPA1):c.2873_2876del AND not provided

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Jan 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000081763.47

Allele description [Variation Report for NM_130837.3(OPA1):c.2873_2876del]

NM_130837.3(OPA1):c.2873_2876del

Gene:

OPA1:OPA1 mitochondrial dynamin like GTPase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3q29

Genomic location:

Preferred name:

NM_130837.3(OPA1):c.2873_2876del

Other names:

p.Val903Glyfs*3

HGVS:

NC_000003.12:g.193667170_193667173del
NG_011605.1:g.79027_79030del
NM_130837.3:c.2873_2876delMANE SELECT
LRG_337t1:c.2708_2711del
LRG_337t2:c.2873_2876del
LRG_337:g.79027_79030del
NC_000003.11:g.193384957_193384960del
NC_000003.11:g.193384959_193384962del
NM_015560.2:c.2708_2711delTTAG
NM_015560.3:c.2708_2711delTTAG
NM_130837.2:c.2873_2876del
NM_130837.2:c.2873_2876delTTAG
NM_130837.3:c.2873-2_2874delMANE SELECT
NP_056375.2:p.Val903GlyfsTer3
p.(Val903Glyfs*3)
p.V903GfsX3

Links:

OMIM: 605290.0003; dbSNP: rs80356530

NCBI 1000 Genomes Browser:

rs80356530

Molecular consequence:

NM_130837.3:c.2873_2876del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000228466	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jan 12, 2017)	germline	clinical testing	Citation Link,
SCV000252013	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 24, 2020)	germline	clinical testing	Citation Link,
SCV000614384	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 7, 2022)	unknown	clinical testing	PubMed (22) [See all records that cite these PMIDs] 25012220, 25641387, 24907432, 20157015, 11810270, 11440989, 12036970, 18222991, 11017079, 21646330, 23250881, 11440988, 16513463, 22857269, 14961560, 15505825, 21636302, 22042570, 20952381, 23401657, 20659957, 26467025
SCV001246487	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2021)	germline	clinical testing	Citation Link,
SCV001446520	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001591733	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11440988, 20157015, 20952381, 25012220, 11017079, 26385429, 28492532
SCV001921462	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001974149	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002818199	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003824243	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 12, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226069	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 21, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11017079, 23250881, 32025183, 33884488, 34242285, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	7	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	26	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction.

Roubertie A, Leboucq N, Picot MC, Nogue E, Brunel H, Le Bars E, Manes G, Angebault Prouteau C, Blanchet C, Mondain M, Chevassus H, Amati-Bonneau P, Sarzi E, Pagès M, Villain M, Meunier I, Lenaers G, Hamel CP.

J Neurol Sci. 2015 Feb 15;349(1-2):154-60. doi: 10.1016/j.jns.2015.01.008. Epub 2015 Jan 13.

PubMed [citation]

PMID:: 25641387

Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation.

Barboni P, Savini G, Cascavilla ML, Caporali L, Milesi J, Borrelli E, La Morgia C, Valentino ML, Triolo G, Lembo A, Carta A, De Negri A, Sadun F, Rizzo G, Parisi V, Pierro L, Bianchi Marzoli S, Zeviani M, Sadun AA, Bandello F, Carelli V.

Am J Ophthalmol. 2014 Sep;158(3):628-36.e3. doi: 10.1016/j.ajo.2014.05.034. Epub 2014 Jun 5.

PubMed [citation]

PMID:: 24907432

See all PubMed Citations (28)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000228466.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	23	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		23	not provided	not provided	not provided

From GeneDx, SCV000252013.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000614384.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246487.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		7	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001591733.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001921462.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001974149.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital, SCV002818199.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003824243.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226069.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (6)

Description

PP1, PS4, PVS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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