NM_130837.3(OPA1):c.1311A>G (p.Ile437Met) AND Abortive cerebellar ataxia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000210748.15

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]

Observations:

Condition(s)

Name:: Abortive cerebellar ataxia (BEHRS)
Synonyms:: OPTIC ATROPHY, INFANTILE HEREDITARY, WITH NEUROLOGIC ABNORMALITIES; Behr syndrome; Optic atrophy, infantile hereditary, Behr complicated form of; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008858; MedGen: C0221061; Orphanet: 1239; OMIM: 210000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266835	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2011)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 17722006, 21636302, 25012220
SCV001366678	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 10, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807267	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048348	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons.

Schimpf S, Fuhrmann N, Schaich S, Wissinger B.

Hum Mutat. 2008 Jan;29(1):106-12.

PubMed [citation]

PMID:: 17722006

Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.

Schaaf CP, Blazo M, Lewis RA, Tonini RE, Takei H, Wang J, Wong LJ, Scaglia F.

Mol Genet Metab. 2011 Aug;103(4):383-7. doi: 10.1016/j.ymgme.2011.04.018. Epub 2011 May 7.

PubMed [citation]

PMID:: 21636302

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000266835.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a patient with autosomal dominant optic atrophy (165500), Schimpf et al. (2008) identified a heterozygous 1146A-G transition in the OPA1 gene, resulting in an ile382-to-met (I382M) substitution at a conserved residue in the GTPase domain. The mutation was not found in 100 controls. No clinical information was provided.

In 2 sibs with Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: I382M and a 4-bp deletion (605290.0003). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) concluded that the missense mutation may be a mild mutation and shows strong additive effects when combined with a second mutation. The more severe phenotype in the children was consistent with autosomal recessive or semidominant inheritance of the disorder.

In 3 unrelated patients with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: each patient carried the I382M substitution in exon 12 on 1 allele and a different mutation on the other allele (see, e.g., 605290.0020). There was no evidence that any of the parents who were heterozygous carriers of the I382M substitution had optic atrophy, but DNA was not available from all asymptomatic parents. Functional studies of the variants were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366678.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP3,PP5.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807267.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PM3 very strong, PP1 supporting, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048348.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.1311A>G p.Ile437Met variant in OPA1 gene has been reported in heterozygous as well as compound heterozygous state in individuals (Schaaf CP et al). Experimental studies have shown a damaging effect (Alessia Nasca et al,2017). This variant is reported with the allele frequency 0.05% in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Likely Pathogenic/Pathogenic/Uncertain Significance/Likely Benign. The amino acid Ile at position 437 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile437Met in OPA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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