VCV000973235.15 - ClinVar

NM_130837.3(OPA1):c.2287del (p.Ser763fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_130837.3(OPA1):c.2287del (p.Ser763fs)

Variation ID: 973235 Accession: VCV000973235.15

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3q29 3: 193657186 (GRCh38) [ NCBI UCSC ] 3: 193374975 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 25, 2020	Sep 16, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_130837.3:c.2287del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570850.2:p.Ser763fs	frameshift
NM_001354663.2:c.1753del	NP_001341592.1:p.Ser585fs	frameshift
NM_001354664.2:c.1750del	NP_001341593.1:p.Ser584fs	frameshift
NM_015560.2:c.2122delA
NM_015560.3:c.2122del	NP_056375.2:p.Ser708fs	frameshift
NM_130831.3:c.2014del	NP_570844.1:p.Ser672fs	frameshift
NM_130832.3:c.2068del	NP_570845.1:p.Ser690fs	frameshift
NM_130833.3:c.2125del	NP_570846.1:p.Ser709fs	frameshift
NM_130834.3:c.2176del	NP_570847.2:p.Ser726fs	frameshift
NM_130835.3:c.2179del	NP_570848.1:p.Ser727fs	frameshift
NM_130836.3:c.2233del	NP_570849.2:p.Ser745fs	frameshift
NC_000003.12:g.193657188del
NC_000003.11:g.193374977del
NG_011605.1:g.69045del
LRG_337:g.69045del
LRG_337t1:c.2122del
LRG_337t2:c.2287del

... more HGVS ... less HGVS

Protein change

S584fs, S585fs, S672fs, S690fs, S708fs, S709fs, S726fs, S727fs, S745fs, S763fs

Other names

Canonical SPDI

NC_000003.12:193657185:AAA:AA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1219753329 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
OPA1		-	-	GRCh38 GRCh37	1349	1547

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Abortive cerebellar ataxia Autosomal dominant optic atrophy classic form Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Pathogenic (1)	criteria provided, single submitter	Sep 20, 2017	RCV001249637.5
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 15, 2023	RCV001587285.10
OPA1-related disorder	Pathogenic (1)	criteria provided, single submitter	Sep 25, 2023	RCV004538529.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 20, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abortive cerebellar ataxia Autosomal dominant optic atrophy classic form Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423604.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020	Comment: [ACMG/AMP: PVS1, PM2] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or … (more) [ACMG/AMP: PVS1, PM2] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2]. (less)
Pathogenic (Jan 21, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002771115.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (2) PubMed: 32371413‚ 21036400 Comment: This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more) This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In some published literature, this variant is referred to as c.2287delA, p.(Ser763ValfsTer15). (less)
Pathogenic (Sep 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	OPA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119705.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The OPA1 c.2287delA variant is predicted to result in a frameshift and premature protein termination (p.Ser763Valfs15). This variant has been reported in the heterozygous state … (more) The OPA1 c.2287delA variant is predicted to result in a frameshift and premature protein termination (p.Ser763Valfs15). This variant has been reported in the heterozygous state in an individual with optic neuropathy (reported as c.2122del in Yu-Wai-Man et al. 2011. PubMed ID: 21036400). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-193374974-GA-G). Frameshift variants in OPA1 are expected to be pathogenic, and this variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/973235). Given the evidence, we too interpret c.2287del (p.Ser763Valfs*15) as pathogenic. (less)
Pathogenic (Oct 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002239002.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 11440988‚ 20157015‚ 20952381‚ 25012220‚ 21036400 Comment: This sequence change creates a premature translational stop signal (p.Ser708Valfs15) in the OPA1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ser708Valfs15) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal dominant optic atrophy (PMID: 21036400). ClinVar contains an entry for this variant (Variation ID: 973235). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001822388.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024	Comment: 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; Not … (more) 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32371413, 35741767, 21036400) (less)

Comment:

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In some published literature, this variant is referred to as c.2287delA, p.(Ser763ValfsTer15).

Comment:

The OPA1 c.2287delA variant is predicted to result in a frameshift and premature protein termination (p.Ser763Valfs*15). This variant has been reported in the heterozygous state in an individual with optic neuropathy (reported as c.2122del in Yu-Wai-Man et al. 2011. PubMed ID: 21036400). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-193374974-GA-G). Frameshift variants in OPA1 are expected to be pathogenic, and this variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/973235). Given the evidence, we too interpret c.2287del (p.Ser763Valfs*15) as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser708Valfs*15) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal dominant optic atrophy (PMID: 21036400). ClinVar contains an entry for this variant (Variation ID: 973235). For these reasons, this variant has been classified as Pathogenic.

Comment:

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32371413, 35741767, 21036400)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.	Miller CR	Cold Spring Harbor molecular case studies	2020	PMID: 32371413
Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.	Bonneau D	Brain : a journal of neurology	2014	PMID: 25012220
Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies.	Yu-Wai-Man P	Ophthalmology	2011	PMID: 21036400
OPA1 mutations impair mitochondrial function in both pure and complicated dominant optic atrophy.	Yu-Wai-Man P	Brain : a journal of neurology	2011	PMID: 20952381
Multi-system neurological disease is common in patients with OPA1 mutations.	Yu-Wai-Man P	Brain : a journal of neurology	2010	PMID: 20157015
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.	Pesch UE	Human molecular genetics	2001	PMID: 11440988

Text-mined citations for rs1219753329 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_130837.3(OPA1):c.2287del (p.Ser763fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1219753329 ...