VCV003377063.1 - ClinVar

NM_130837.3(OPA1):c.1053T>A (p.Asp351Glu)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_130837.3(OPA1):c.1053T>A (p.Asp351Glu)

Variation ID: 3377063 Accession: VCV003377063.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q29 3: 193637969 (GRCh38) [ NCBI UCSC ] 3: 193355758 (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	Nov 25, 2024	Nov 24, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_130837.3:c.1053T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570850.2:p.Asp351Glu	missense
NM_001354663.2:c.519T>A	NP_001341592.1:p.Asp173Glu	missense
NM_001354664.2:c.516T>A	NP_001341593.1:p.Asp172Glu	missense
NM_015560.3:c.888T>A	NP_056375.2:p.Asp296Glu	missense
NM_130831.3:c.780T>A	NP_570844.1:p.Asp260Glu	missense
NM_130832.3:c.834T>A	NP_570845.1:p.Asp278Glu	missense
NM_130833.3:c.891T>A	NP_570846.1:p.Asp297Glu	missense
NM_130834.3:c.942T>A	NP_570847.2:p.Asp314Glu	missense
NM_130835.3:c.945T>A	NP_570848.1:p.Asp315Glu	missense
NM_130836.3:c.999T>A	NP_570849.2:p.Asp333Glu	missense
NC_000003.12:g.193637969T>A
NC_000003.11:g.193355758T>A
NG_011605.1:g.49826T>A
LRG_337:g.49826T>A
LRG_337t1:c.888T>A	LRG_337p1:p.Asp296Glu
LRG_337t2:c.1053T>A	LRG_337p2:p.Asp351Glu

... more HGVS ... less HGVS

Protein change

D172E, D173E, D260E, D278E, D296E, D297E, D314E, D315E, D333E, D351E

Other names

Canonical SPDI

NC_000003.12:193637968:T:A

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

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	1279	1471

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.
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Pathogenic (1)	criteria provided, single submitter	Oct 9, 2024	RCV004788677.1

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 (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399738.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (6) PubMed: 17306754‚ 25012220‚ 26194196‚ 28494813‚ 30165240‚ 31500643 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants are clustered within the GTPase domain, generally develop optic atrophy plus syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome (PMID: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change, p.(Asp351His), has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been described in a family with with autosomal dominant optic atrophy plus syndrome (PMID: 26194196). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a family with eight affected relatives with autosomal dominant optic atrophy plus syndrome (PMID: 26194196). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants are clustered within the GTPase domain, generally develop optic atrophy plus syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome (PMID: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change, p.(Asp351His), has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been described in a family with with autosomal dominant optic atrophy plus syndrome (PMID: 26194196). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a family with eight affected relatives with autosomal dominant optic atrophy plus syndrome (PMID: 26194196). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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: 516 unique variants and 831 patients registered in an updated centralized Variome database.	Le Roux B	Orphanet journal of rare diseases	2019	PMID: 31500643
Meta-analysis of genotype-phenotype analysis of OPA1 mutations in autosomal dominant optic atrophy.	Ham M	Mitochondrion	2019	PMID: 30165240
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.	Nasca A	Orphanet journal of rare diseases	2017	PMID: 28494813
A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family.	Ahmad KE	Journal of neurology	2015	PMID: 26194196
Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.	Bonneau D	Brain : a journal of neurology	2014	PMID: 25012220
Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations.	Cohn AC	American journal of ophthalmology	2007	PMID: 17306754

Text-mined citations for this variant ...

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_130837.3(OPA1):c.1053T>A (p.Asp351Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...