NM_130837.3(OPA1):c.1034G>A (p.Arg345Gln) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 3, 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:: RCV000790668.19

Allele description [Variation Report for NM_130837.3(OPA1):c.1034G>A (p.Arg345Gln)]

NM_130837.3(OPA1):c.1034G>A (p.Arg345Gln)

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.1034G>A (p.Arg345Gln)

Other names:

R290Q

HGVS:

NC_000003.12:g.193637280G>A
NG_011605.1:g.49137G>A
NM_001354663.2:c.500G>A
NM_001354664.2:c.497G>A
NM_015560.3:c.869G>A
NM_130831.3:c.761G>A
NM_130832.3:c.815G>A
NM_130833.3:c.872G>A
NM_130834.3:c.923G>A
NM_130835.3:c.926G>A
NM_130836.3:c.980G>A
NM_130837.3:c.1034G>AMANE SELECT
NP_001341592.1:p.Arg167Gln
NP_001341593.1:p.Arg166Gln
NP_056375.2:p.Arg290Gln
NP_570844.1:p.Arg254Gln
NP_570845.1:p.Arg272Gln
NP_570846.1:p.Arg291Gln
NP_570847.2:p.Arg308Gln
NP_570848.1:p.Arg309Gln
NP_570849.2:p.Arg327Gln
NP_570850.2:p.Arg345Gln
LRG_337t1:c.869G>A
LRG_337:g.49137G>A
LRG_337p1:p.Arg290Gln
NC_000003.11:g.193355069G>A
NM_015560.2:c.869G>A
O60313:p.Arg290Gln

Protein change:

R166Q; ARG290GLN

Links:

UniProtKB: O60313#VAR_011483; OMIM: 605290.0005; dbSNP: rs121908375

NCBI 1000 Genomes Browser:

rs121908375

Molecular consequence:

NM_001354663.2:c.500G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354664.2:c.497G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015560.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130831.3:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130832.3:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130833.3:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130834.3:c.923G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130835.3:c.926G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130836.3:c.980G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_130837.3:c.1034G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000232749	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jan 6, 2016)	germline	clinical testing	Citation Link,
SCV001762175	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001787297	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 29, 2020)	germline	clinical testing	Citation Link,
SCV001880554	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Feb 19, 2021)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11810270, 11440988, 11440989, 22779427, 17167772, 21745197, 23916084, 17722006, 27858935, 30293569, 32379273, 24907432, 11017080, 26467025
SCV003525477	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11017080, 11440988, 11810270, 22779427, 25564500, 17167772, 26867657, 28492532

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	1	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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

Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.

Toomes C, Marchbank NJ, Mackey DA, Craig JE, Newbury-Ecob RA, Bennett CP, Vize CJ, Desai SP, Black GC, Patel N, Teimory M, Markham AF, Inglehearn CF, Churchill AJ.

Hum Mol Genet. 2001 Jun 15;10(13):1369-78.

PubMed [citation]

PMID:: 11440989

See all PubMed Citations (18)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000232749.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001762175.1

#	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 GeneDx, SCV001787297.1

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

Description

Functional studies support a deleterious effect on mitochondrial morphology and cellular reactive oxygen species level (Zhang et al., 2016; Olichon et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33300680, 27858935, 30293569, 22779427, 21745197, 23916084, 25564500, 11017080, 17167772, 26867657, 32025183)

#	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 Inc, SCV001880554.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study in mouse embryonic fibroblasts showed this variant caused significant decrease of mtDNA content and completely fragmented the mitochondrial network (PMID: 30293569). The variant is located in a region that is considered important for protein function and/or structure.

#	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 Invitae, SCV003525477.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 290 of the OPA1 protein (p.Arg290Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant optic atrophy (PMID: 11017080, 11440988, 11810270, 22779427, 25564500). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg345Gln. ClinVar contains an entry for this variant (Variation ID: 5084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects OPA1 function (PMID: 17167772, 26867657). 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

Last Updated: Apr 15, 2024

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