NM_130837.3(OPA1):c.1150-2A>G AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV000368869.9

Allele description

NM_130837.3(OPA1):c.1150-2A>G

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3q29

Genomic location:

Preferred name:

NM_130837.3(OPA1):c.1150-2A>G

HGVS:

NC_000003.12:g.193642763A>G
NG_011605.1:g.54620A>G
NM_001354663.2:c.616-2A>G
NM_001354664.2:c.613-2A>G
NM_015560.3:c.985-2A>G
NM_130831.3:c.877-2A>G
NM_130832.3:c.931-2A>G
NM_130833.3:c.988-2A>G
NM_130834.3:c.1039-2A>G
NM_130835.3:c.1042-2A>G
NM_130836.3:c.1096-2A>G
NM_130837.3:c.1150-2A>GMANE SELECT
LRG_337t1:c.985-2A>G
LRG_337:g.54620A>G
NC_000003.11:g.193360552A>G
NM_015560.2:c.985-2A>G

Links:

dbSNP: rs886041317

NCBI 1000 Genomes Browser:

rs886041317

Molecular consequence:

NM_001354663.2:c.616-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354664.2:c.613-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_015560.3:c.985-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130831.3:c.877-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130832.3:c.931-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130833.3:c.988-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130834.3:c.1039-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130835.3:c.1042-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130836.3:c.1096-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_130837.3:c.1150-2A>G - 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
SCV000329705	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 21, 2023)	germline	clinical testing	Citation Link,
SCV000344349	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Aug 17, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19112530, 22197506 Citation Link,
SCV002238178	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19112530, 22197506, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329705

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 21, 2023)

germline

clinical testing

Citation Link,

SCV000344349

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Aug 17, 2016)

germline

clinical testing

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

Citation Link,

SCV002238178

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of two novel OPA1 mutations in Chinese families with autosomal dominant optic atrophy.

Li Y, Deng T, Tong Y, Peng S, Dong B, He D.

Mol Vis. 2008;14:2451-7. Epub 2008 Dec 29.

PubMed [citation]

PMID:: 19112530
PMCID:: PMC2610289

Optic atrophy plus phenotype due to mutations in the OPA1 gene: two more Italian families.

Ranieri M, Del Bo R, Bordoni A, Ronchi D, Colombo I, Riboldi G, Cosi A, Servida M, Magri F, Moggio M, Bresolin N, Comi GP, Corti S.

J Neurol Sci. 2012 Apr 15;315(1-2):146-9. doi: 10.1016/j.jns.2011.12.002. Epub 2011 Dec 22.

PubMed [citation]

PMID:: 22197506
PMCID:: PMC3315002

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000329705.6

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

Description

Published functional studies demonstrate that this variant results in exon skipping resulting in the loss of 27 amino acids (Li et al., 2008); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205859, 25525159, 19112530, 22197506)

#	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 Eurofins Ntd Llc (ga), SCV000344349.4

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

#	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		2	not provided	not provided	not provided

From Invitae, SCV002238178.3

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 19112530, 22197506). ClinVar contains an entry for this variant (Variation ID: 280005). Disruption of this splice site has been observed in individuals with autosomal dominant optic atrophy (PMID: 19112530, 22197506). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the OPA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

#	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: Feb 14, 2024

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