VCV003377425.1 - ClinVar

NM_130837.3(OPA1):c.1291A>G (p.Thr431Ala)

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.

Likely 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.1291A>G (p.Thr431Ala)

Variation ID: 3377425 Accession: VCV003377425.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q29 3: 193643035 (GRCh38) [ NCBI UCSC ] 3: 193360824 (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	May 6, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_130837.3:c.1291A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570850.2:p.Thr431Ala	missense
NM_001354663.2:c.757A>G	NP_001341592.1:p.Thr253Ala	missense
NM_001354664.2:c.754A>G	NP_001341593.1:p.Thr252Ala	missense
NM_015560.3:c.1126A>G	NP_056375.2:p.Thr376Ala	missense
NM_130831.3:c.1018A>G	NP_570844.1:p.Thr340Ala	missense
NM_130832.3:c.1072A>G	NP_570845.1:p.Thr358Ala	missense
NM_130833.3:c.1129A>G	NP_570846.1:p.Thr377Ala	missense
NM_130834.3:c.1180A>G	NP_570847.2:p.Thr394Ala	missense
NM_130835.3:c.1183A>G	NP_570848.1:p.Thr395Ala	missense
NM_130836.3:c.1237A>G	NP_570849.2:p.Thr413Ala	missense
NC_000003.12:g.193643035A>G
NC_000003.11:g.193360824A>G
NG_011605.1:g.54892A>G
LRG_337:g.54892A>G
LRG_337t1:c.1126A>G	LRG_337p1:p.Thr376Ala
LRG_337t2:c.1291A>G	LRG_337p2:p.Thr431Ala

... more HGVS ... less HGVS

Protein change

T252A, T253A, T340A, T358A, T376A, T377A, T394A, T395A, T413A, T431A

Other names

Canonical SPDI

NC_000003.12:193643034:A:G

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	1353	1554

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	Likely pathogenic (1)	criteria provided, single submitter	May 6, 2021	RCV004790016.1

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.
Likely pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399217.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 11855928‚ 17306754‚ 21731710‚ 25012220‚ 28494813‚ 30165240‚ 31500643 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant which is in the same haplotype as the p.I313E variant, is classified as likely pathogenic. Following criteria … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant which is in the same haplotype as the p.I313E variant, is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Behr syndrome (MIM#210000), optic atrophy 1 (MIM#165500) and syndromic optic atrophy (MIM#125250). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and pathogenic variants in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants that are clustered within the GTPase domain generally develop syndromic optic atrophy. 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 and has been reported for optic atrophy 1 (MIM#165500) (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GTPase domain (PMID: 11855928). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0901 - This variant has strong evidence for segregation with disease. This variant, shown to be in cis with the p.I313E variant, has been reported to segregate in 51 family members with 100% penetrance (PMID: 17306754). (SP) 1010 - Functional evidence for this variant is inconclusive. Although Vanbergen et al (2011) demonstrated reduced OPA1 protein levels and impaired OXPHOS efficiency, their experiments were performed on combined total protein lysates from lymphoblastoid cell lines generated from multiple carriers of pathogenic variants, including a cell line carrying both p.T376A and p.I313E. Therefore, it is difficult to determine the specific functional consequence of our variant of interest (PMID: 21731710). (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 which is in the same haplotype as the p.I313E variant, is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Behr syndrome (MIM#210000), optic atrophy 1 (MIM#165500) and syndromic optic atrophy (MIM#125250). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and pathogenic variants in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants that are clustered within the GTPase domain generally develop syndromic optic atrophy. 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 and has been reported for optic atrophy 1 (MIM#165500) (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GTPase domain (PMID: 11855928). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0901 - This variant has strong evidence for segregation with disease. This variant, shown to be in cis with the p.I313E variant, has been reported to segregate in 51 family members with 100% penetrance (PMID: 17306754). (SP) 1010 - Functional evidence for this variant is inconclusive. Although Vanbergen et al (2011) demonstrated reduced OPA1 protein levels and impaired OXPHOS efficiency, their experiments were performed on combined total protein lysates from lymphoblastoid cell lines generated from multiple carriers of pathogenic variants, including a cell line carrying both p.T376A and p.I313E. Therefore, it is difficult to determine the specific functional consequence of our variant of interest (PMID: 21731710). (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
Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.	Bonneau D	Brain : a journal of neurology	2014	PMID: 25012220
Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.	Van Bergen NJ	PloS one	2011	PMID: 21731710
Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations.	Cohn AC	American journal of ophthalmology	2007	PMID: 17306754
OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease.	Delettre C	Molecular genetics and metabolism	2002	PMID: 11855928

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.1291A>G (p.Thr431Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...