NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 19, 2022
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:: RCV001659726.5

Allele description [Variation Report for NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg)]

NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg)

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.1800C>G (p.Ser600Arg)

HGVS:

NC_000003.12:g.193647110C>G
NG_011605.1:g.58967C>G
NM_001354663.2:c.1266C>G
NM_001354664.2:c.1263C>G
NM_015560.3:c.1635C>G
NM_130831.3:c.1527C>G
NM_130832.3:c.1581C>G
NM_130833.3:c.1638C>G
NM_130834.3:c.1689C>G
NM_130835.3:c.1692C>G
NM_130836.3:c.1746C>G
NM_130837.3:c.1800C>GMANE SELECT
NP_001341592.1:p.Ser422Arg
NP_001341593.1:p.Ser421Arg
NP_056375.2:p.Ser545Arg
NP_056375.2:p.Ser545Arg
NP_570844.1:p.Ser509Arg
NP_570845.1:p.Ser527Arg
NP_570846.1:p.Ser546Arg
NP_570847.2:p.Ser563Arg
NP_570848.1:p.Ser564Arg
NP_570849.2:p.Ser582Arg
NP_570850.2:p.Ser600Arg
LRG_337t1:c.1635C>G
LRG_337:g.58967C>G
LRG_337p1:p.Ser545Arg
NC_000003.11:g.193364899C>G
NM_015560.2:c.1635C>G

Protein change:

S421R; SER545ARG

Links:

OMIM: 605290.0015; dbSNP: rs398124298

NCBI 1000 Genomes Browser:

rs398124298

Molecular consequence:

NM_001354663.2:c.1266C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354664.2:c.1263C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015560.3:c.1635C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130831.3:c.1527C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130832.3:c.1581C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130833.3:c.1638C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130834.3:c.1689C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130835.3:c.1692C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130836.3:c.1746C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_130837.3:c.1800C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PDE9A [Fulmarus glacialis]
PDE9A [Fulmarus glacialis]
Gene ID:104074210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001880546	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Jan 25, 2021)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18065439, 18158317, 20185555, 20157015, 22433900, 20417570, 19319978, 28378518, 30293569, 26467025
SCV002236722	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 19, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18065439, 18158317, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001880546

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Pathogenic
(Jan 25, 2021)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002236722

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 19, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.

Ban T, Heymann JA, Song Z, Hinshaw JE, Chan DC.

Hum Mol Genet. 2010 Jun 1;19(11):2113-22. doi: 10.1093/hmg/ddq088. Epub 2010 Feb 25.

PubMed [citation]

PMID:: 20185555
PMCID:: PMC2865371

Multi-system neurological disease is common in patients with OPA1 mutations.

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, et al.

Brain. 2010 Mar;133(Pt 3):771-86. doi: 10.1093/brain/awq007. Epub 2010 Feb 15.

PubMed [citation]

PMID:: 20157015
PMCID:: PMC2842512

See all PubMed Citations (11)

Details of each submission

From Athena Diagnostics, SCV001880546.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced the protein's GTP hydrolysis activity (PMID: 20185555, 30293569).

#	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 Invitae, SCV002236722.3

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

Description

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OPA1 protein function. ClinVar contains an entry for this variant (Variation ID: 30461). This missense change has been observed in individual(s) with autosomal dominant OPA1-related conditions (PMID: 18065439, 18158317). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 545 of the OPA1 protein (p.Ser545Arg).

#	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 16, 2024

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