NM_130837.3(OPA1):c.1466T>C (p.Leu489Pro) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 13, 2022
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:: RCV000497888.11

Allele description [Variation Report for NM_130837.3(OPA1):c.1466T>C (p.Leu489Pro)]

NM_130837.3(OPA1):c.1466T>C (p.Leu489Pro)

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.1466T>C (p.Leu489Pro)

HGVS:

NC_000003.12:g.193643616T>C
NG_011605.1:g.55473T>C
NM_001354663.2:c.932T>C
NM_001354664.2:c.929T>C
NM_015560.3:c.1301T>C
NM_130831.3:c.1193T>C
NM_130832.3:c.1247T>C
NM_130833.3:c.1304T>C
NM_130834.3:c.1355T>C
NM_130835.3:c.1358T>C
NM_130836.3:c.1412T>C
NM_130837.3:c.1466T>CMANE SELECT
NP_001341592.1:p.Leu311Pro
NP_001341593.1:p.Leu310Pro
NP_056375.2:p.Leu434Pro
NP_056375.2:p.Leu434Pro
NP_570844.1:p.Leu398Pro
NP_570845.1:p.Leu416Pro
NP_570846.1:p.Leu435Pro
NP_570847.2:p.Leu452Pro
NP_570848.1:p.Leu453Pro
NP_570849.2:p.Leu471Pro
NP_570850.2:p.Leu489Pro
LRG_337t1:c.1301T>C
LRG_337:g.55473T>C
LRG_337p1:p.Leu434Pro
NC_000003.11:g.193361405T>C
NM_015560.2:c.1301T>C

Protein change:

L310P

Links:

dbSNP: rs1553877946

NCBI 1000 Genomes Browser:

rs1553877946

Molecular consequence:

NM_001354663.2:c.932T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354664.2:c.929T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_015560.3:c.1301T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130831.3:c.1193T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130832.3:c.1247T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130833.3:c.1304T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130834.3:c.1355T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130835.3:c.1358T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130836.3:c.1412T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_130837.3:c.1466T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589881	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jun 10, 2016)	germline	clinical testing	Citation Link,
SCV000702813	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Nov 15, 2016)	germline	clinical testing	Citation Link,
SCV002771119	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Aug 5, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34242285, 29952689, 26467025
SCV004540395	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30201499, 29952689, 34242285, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Genetic analysis in a cohort of patients with hereditary optic neuropathies in Southwest of China.

Guo H, Li S, Dai L, Huang X, Yu T, Yin Z, Bai Y.

Mitochondrion. 2019 May;46:327-333. doi: 10.1016/j.mito.2018.09.002. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30201499

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000589881.2

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

Description

The L434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L434P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L434P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N430D, I432V, C435Y, Q437R, D438G/A/V, G439V) have been reported in the Human Gene Mutation Database in association with optic atrophy 1, multiple mitochondrial DNA deletion disorder, optic atrophy with deafness, and optic atrophy with deafness and ataxia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

#	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

From Eurofins Ntd Llc (ga), SCV000702813.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Athena Diagnostics, SCV002771119.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004540395.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu434 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30201499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OPA1 protein function. ClinVar contains an entry for this variant (Variation ID: 432190). This variant is also known as p.L489P. This missense change has been observed in individuals with clinical features of OPA1-related conditions (PMID: 29952689, 34242285). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 434 of the OPA1 protein (p.Leu434Pro).

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

Last Updated: Sep 29, 2024

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