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NM_130837.3(OPA1):c.1766T>G (p.Leu589Arg) AND Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 15, 2021
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000210746.9

Allele description [Variation Report for NM_130837.3(OPA1):c.1766T>G (p.Leu589Arg)]

NM_130837.3(OPA1):c.1766T>G (p.Leu589Arg)

Genes:
LOC126806913:BRD4-independent group 4 enhancer GRCh37_chr3:193364377-193365576 [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.1766T>G (p.Leu589Arg)
HGVS:
  • NC_000003.12:g.193647076T>G
  • NG_011605.1:g.58933T>G
  • NM_001354663.2:c.1232T>G
  • NM_001354664.2:c.1229T>G
  • NM_015560.3:c.1601T>G
  • NM_130831.3:c.1493T>G
  • NM_130832.3:c.1547T>G
  • NM_130833.3:c.1604T>G
  • NM_130834.3:c.1655T>G
  • NM_130835.3:c.1658T>G
  • NM_130836.3:c.1712T>G
  • NM_130837.3:c.1766T>GMANE SELECT
  • NP_001341592.1:p.Leu411Arg
  • NP_001341593.1:p.Leu410Arg
  • NP_056375.2:p.Leu534Arg
  • NP_570844.1:p.Leu498Arg
  • NP_570845.1:p.Leu516Arg
  • NP_570846.1:p.Leu535Arg
  • NP_570847.2:p.Leu552Arg
  • NP_570848.1:p.Leu553Arg
  • NP_570849.2:p.Leu571Arg
  • NP_570850.2:p.Leu589Arg
  • LRG_337:g.58933T>G
  • NC_000003.11:g.193364865T>G
Protein change:
L410R; LEU534ARG
Links:
OMIM: 605290.0023; dbSNP: rs869312995
NCBI 1000 Genomes Browser:
rs869312995
Molecular consequence:
  • NM_001354663.2:c.1232T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354664.2:c.1229T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015560.3:c.1601T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130831.3:c.1493T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130832.3:c.1547T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130833.3:c.1604T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130834.3:c.1655T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130835.3:c.1658T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130836.3:c.1712T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_130837.3:c.1766T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (MTDPS14)
Synonyms:
Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type)
Identifiers:
MONDO: MONDO:0014820; MedGen: C4225163; OMIM: 616896

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000266840OMIM
no assertion criteria provided
Pathogenic
(Oct 15, 2021) 		germlineliterature only

Spiegel, R., Saada, A., Flannery, P. J., Burte, F., Soiferman, D., Khayat, M., Eisner, V., Vladovski, E., Taylor, R. W., Bindoff, L. A., Shaag, A., Mandel, H., Schuler-Furman, O., Shalev, S. A., Elpeleg, O., Yu-Wai-Man, P. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J. Med. Genet. 53: 127-131, 2016.

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Details of each submission

From OMIM, SCV000266840.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided

Description

In 2 sisters, born of consanguineous Arab parents, with mitochondrial DNA depletion syndrome-14 (MTDPS14; 616896), Spiegel et al. (2016) identified a homozygous c.1601T-G transversion (c.1601T-G, NM_015560.2) in the OPA1 gene, resulting in a leu534-to-arg (L534R) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the ExAC database or in 120 ethnically matched controls. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. The patients showed hypotonia, peripheral hypertonia, profound neurodevelopmental delay, optic atrophy, and normal lactate. Both developed progressive hypertrophic cardiomyopathy and died in infancy. Skeletal muscle biopsies showed a global decrease in all mitochondrial respiratory chain activities, with complexes I and IV being the most affected, as well as significant mtDNA depletion, with a 78% decrease compared to controls. Electron microscopy of 1 patient showed large mitochondria with incomplete fusion of the inner mitochondrial membrane. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities.

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

Last Updated: Mar 26, 2023