NM_025136.4(OPA3):c.81del (p.Lys28fs) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 13, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002638643.1

Allele description [Variation Report for NM_025136.4(OPA3):c.81del (p.Lys28fs)]

NM_025136.4(OPA3):c.81del (p.Lys28fs)

Genes:

LOC130064709:ATAC-STARR-seq lymphoblastoid active region 14802 [Gene]
OPA3:outer mitochondrial membrane lipid metabolism regulator OPA3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_025136.4(OPA3):c.81del (p.Lys28fs)

HGVS:

NC_000019.10:g.45584685del
NG_013332.1:g.5181del
NM_001017989.3:c.81del
NM_025136.4:c.81delMANE SELECT
NP_001017989.2:p.Lys28fs
NP_079412.1:p.Lys28Argfs
NP_079412.1:p.Lys28fs
NC_000019.9:g.46087942del
NC_000019.9:g.46087943del
NM_025136.2:c.80delT

Protein change:

K28fs

Molecular consequence:

NM_001017989.3:c.81del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_025136.4:c.81del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: 3-Methylglutaconic aciduria type 3 (MGCA3)
Synonyms:: OPA3, AUTOSOMAL RECESSIVE; OPTIC ATROPHY 3, AUTOSOMAL RECESSIVE; 3-methylglutaconic aciduria type III; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009787; MedGen: C0574084; Orphanet: 67047; OMIM: 258501

Name:: Optic atrophy 3 (OPA3)
Synonyms:: OPTIC ATROPHY 3, AUTOSOMAL DOMINANT; Optic atrophy and cataract, autosomal dominant; Optic atrophy, cataract, and neurologic disorder
Identifiers:: MONDO: MONDO:0008133; MedGen: C1833809; Orphanet: 67036; OMIM: 165300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002971101	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18985435, 27629047, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002971101

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 13, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Costeff optic atrophy syndrome: new clinical case and novel molecular findings.

Ho G, Walter JH, Christodoulou J.

J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S419-23. doi: 10.1007/s10545-008-0981-z. Epub 2008 Nov 7. Review.

PubMed [citation]

PMID:: 18985435

Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia.

Alfadhel M, Benmeakel M, Hossain MA, Al Mutairi F, Al Othaim A, Alfares AA, Al Balwi M, Alzaben A, Eyaid W.

Orphanet J Rare Dis. 2016 Sep 15;11(1):126. doi: 10.1186/s13023-016-0510-3.

PubMed [citation]

PMID:: 27629047
PMCID:: PMC5024448

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002971101.1

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

Description

This sequence change creates a premature translational stop signal (p.Lys28Argfs*44) in the OPA3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the OPA3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OPA3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the C-terminus of the OPA3 protein. Other variant(s) that disrupt this region (p.Gly65Alafs*7, p.Gln139*) have been observed in individuals with OPA3-related conditions (PMID: 18985435, 27629047). This suggests that this may be a clinically significant region of the protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Oct 14, 2023

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