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NM_130837.3(OPA1):c.1311A>G (p.Ile437Met) AND OPA1-related disorder

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 17, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV004537182.3

Allele description [Variation Report for NM_130837.3(OPA1):c.1311A>G (p.Ile437Met)]

NM_130837.3(OPA1):c.1311A>G (p.Ile437Met)

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.1311A>G (p.Ile437Met)
Other names:
I382M
HGVS:
  • NC_000003.12:g.193643378A>G
  • NG_011605.1:g.55235A>G
  • NM_001354663.2:c.777A>G
  • NM_001354664.2:c.774A>G
  • NM_015560.3:c.1146A>G
  • NM_130831.3:c.1038A>G
  • NM_130832.3:c.1092A>G
  • NM_130833.3:c.1149A>G
  • NM_130834.3:c.1200A>G
  • NM_130835.3:c.1203A>G
  • NM_130836.3:c.1257A>G
  • NM_130837.3:c.1311A>GMANE SELECT
  • NP_001341592.1:p.Ile259Met
  • NP_001341593.1:p.Ile258Met
  • NP_056375.2:p.Ile382Met
  • NP_056375.2:p.Ile382Met
  • NP_570844.1:p.Ile346Met
  • NP_570845.1:p.Ile364Met
  • NP_570846.1:p.Ile383Met
  • NP_570847.2:p.Ile400Met
  • NP_570848.1:p.Ile401Met
  • NP_570849.2:p.Ile419Met
  • NP_570850.2:p.Ile437Met
  • NP_570850.2:p.Ile437Met
  • LRG_337t1:c.1146A>G
  • LRG_337t2:c.1311A>G
  • LRG_337:g.55235A>G
  • LRG_337p1:p.Ile382Met
  • LRG_337p2:p.Ile437Met
  • NC_000003.11:g.193361167A>G
  • NM_015560.2:c.1146A>G
  • NM_130833.1:c.1149A>G
  • NM_130837.2:c.1311A>G
  • NM_130837.3:c.1311A>G
  • O60313:p.Ile382Met
  • p.I382M
Protein change:
I258M; ILE382MET
Links:
UniProtKB: O60313#VAR_060837; OMIM: 605290.0018; dbSNP: rs143319805
NCBI 1000 Genomes Browser:
rs143319805
Molecular consequence:
  • NM_001354663.2:c.777A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354664.2:c.774A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015560.3:c.1146A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130831.3:c.1038A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130832.3:c.1092A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130833.3:c.1149A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130834.3:c.1200A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130835.3:c.1203A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130836.3:c.1257A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130837.3:c.1311A>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
variation affecting protein [Variation Ontology: 0002]

Condition(s)

Name:
OPA1-related disorder
Synonyms:
OPA1-related condition; OPA1 related disorders
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004740804PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 12, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005049782Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 17, 2024) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004740804.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The OPA1 c.1311A>G variant is predicted to result in the amino acid substitution p.Ile437Met. This variant (also known as c.1146A>G [p.Ile382Met] in transcript NM_015560.2) has been reported in the heterozygous state in patients with autosomal dominant optic atrophy (Schimpf et al. 2008. PubMed ID: 17722006; Ferré et al. 2009. PubMed ID: 19319978; Carelli et al. 2015. PubMed ID: 25146916). However, other individuals who carried this variant in the heterozygous or even homozygous states were reportedly asymptomatic (Bonifert et al. 2014. PubMed ID: 24970096; Bonneau et al. 2014. PubMed ID: 25012220; Carelli et al. 2015. PubMed ID: 25146916). Several reports indicate that this variant may possibly be a mild pathogenic variant that contributes to increased severity of disease when present in the compound heterozygous state with a known pathogenic variant (Bonifert et al. 2014. PubMed ID: 24970096; Bonneau et al. 2014. PubMed ID: 25012220; Nasca et al. 2017. PubMed ID: 28494813). This variant has been classified as likely benign, uncertain, likely pathogenic, and pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/50866). This variant is reported in 0.098% of alleles in individuals of South Asian descent in gnomAD, including >150 heterozygotes in the entire gnomAD population database. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV005049782.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024