NM_130837.3(OPA1):c.2873_2876del AND OPA1-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 18, 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:: RCV004532291.3

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]

Condition(s)

Name:: OPA1-related disorder
Synonyms:: OPA1-related condition; OPA1 related disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004120905	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 31, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005061372	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 18, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17306754, 18222991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004120905

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 31, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005061372

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 18, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations.

Cohn AC, Toomes C, Potter C, Towns KV, Hewitt AW, Inglehearn CF, Craig JE, Mackey DA.

Am J Ophthalmol. 2007 Apr;143(4):656-62. Epub 2007 Feb 15.

PubMed [citation]

PMID:: 17306754

See all PubMed Citations (3)

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004120905.1

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

Description

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.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005061372.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	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

Last Updated: Aug 4, 2024

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