VCV000095711.17 - ClinVar

NM_130837.3(OPA1):c.1773A>C (p.Ala591=)

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.

(9)

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.

Benign

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.1773A>C (p.Ala591=)

Variation ID: 95711 Accession: VCV000095711.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q29 3: 193647083 (GRCh38) [ NCBI UCSC ] 3: 193364872 (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	Oct 2, 2016	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_130837.3:c.1773A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570850.2:p.Ala591=	synonymous
NM_001354663.2:c.1239A>C	NP_001341592.1:p.Ala413=	synonymous
NM_001354664.2:c.1236A>C	NP_001341593.1:p.Ala412=	synonymous
NM_015560.3:c.1608A>C	NP_056375.2:p.Ala536=	synonymous
NM_130831.3:c.1500A>C	NP_570844.1:p.Ala500=	synonymous
NM_130832.3:c.1554A>C	NP_570845.1:p.Ala518=	synonymous
NM_130833.3:c.1611A>C	NP_570846.1:p.Ala537=	synonymous
NM_130834.3:c.1662A>C	NP_570847.2:p.Ala554=	synonymous
NM_130835.3:c.1665A>C	NP_570848.1:p.Ala555=	synonymous
NM_130836.3:c.1719A>C	NP_570849.2:p.Ala573=	synonymous
NC_000003.12:g.193647083A>C
NC_000003.11:g.193364872A>C
NG_011605.1:g.58940A>C
LRG_337:g.58940A>C
LRG_337t1:c.1608A>C	LRG_337p1:p.Ala536=
LRG_337t2:c.1773A>C	LRG_337p2:p.Ala591=

... more HGVS ... less HGVS

Protein change

Other names

p.A536A:GCA>GCC

Canonical SPDI

NC_000003.12:193647082:A:C

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.

0.02736 (C)

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

The Genome Aggregation Database (gnomAD), exomes 0.02563

Exome Aggregation Consortium (ExAC) 0.02669

1000 Genomes Project 0.02736

Trans-Omics for Precision Medicine (TOPMed) 0.02958

1000 Genomes Project 30x 0.03014

The Genome Aggregation Database (gnomAD) 0.03184

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03191

Links

ClinGen: CA285701 dbSNP: rs78767626 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.
LOC126806913	-	-	-	GRCh38	-	64
OPA1		-	-	GRCh38 GRCh37	1269	1460

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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2017	RCV000081751.15
Autosomal dominant optic atrophy classic form	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000319475.5
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000676698.10
Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)	Benign (1)	criteria provided, single submitter	May 4, 2023	RCV003993798.1

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000315378.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 01, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614378.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (4) PubMed: 19581274‚ 11440989‚ 16785854‚ 11440988
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442629.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Nov 29, 2011)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170839.12 First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 31, 2024)	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: SCV001723477.3 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005303708.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Apr 06, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000113686.8 First in ClinVar: Jan 23, 2014 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1 Number of individuals with the variant: 22 Sex: mixed
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812818.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: African/African American population allele frequency is 3.549% (rs78767626, 951/24904 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, … (more) African/African American population allele frequency is 3.549% (rs78767626, 951/24904 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Benign (Feb 23, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000802496.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

African/African American population allele frequency is 3.549% (rs78767626, 951/24904 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1

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
OPA1 increases the risk of normal but not high tension glaucoma.	Yu-Wai-Man P	Journal of medical genetics	2010	PMID: 19581274
Evaluation of the association between OPA1 polymorphisms and primary open-angle glaucoma in Barbados families.	Yao W	Molecular vision	2006	PMID: 16785854
Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.	Toomes C	Human molecular genetics	2001	PMID: 11440989
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.	Pesch UE	Human molecular genetics	2001	PMID: 11440988
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1	-	-	-	-

Text-mined citations for rs78767626 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_130837.3(OPA1):c.1773A>C (p.Ala591=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs78767626 ...