rs863224906

chr3-193657197-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_130837.3(OPA1):c.2296C>T(p.Arg766Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OPA1 NM_130837.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.02

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

LOC102724808 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-193657197-C-T is Pathogenic according to our data. Variant chr3-193657197-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193657197-C-T is described in Lovd as [Pathogenic]. Variant chr3-193657197-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.2296C>T	p.Arg766Ter	stop_gained	23/31	ENST00000361510.8
LOC102724808	XR_924835.3	n.421-9887G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.2296C>T	p.Arg766Ter	stop_gained	23/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change creates a premature translational stop signal (p.Arg711*) in the OPA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OPA1 are known to be pathogenic (PMID: 11440988, 20157015, 20952381, 25012220). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with optic atrophy (PMID: 11810270). ClinVar contains an entry for this variant (Variation ID: 216979). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2018	The OPA1 c.2296C>T; p.Arg766Ter variant (rs863224906; ClinVar Variation ID: 216979) has been previously identified in an individual with a personal and family consistent with dominantly inherited optic atrophy (Delettre 2001). Located in exon 23 (of 31) is variant is expected to result in a truncated or absent protein product. Additionally, this variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). As loss of function is an established disease mechanism in OPA1-mediated optic atrophy, based on the available information, this variant is considered pathogenic. Pathogenic variants in OPA1 are associated with autosomal dominant optic atrophy 1 (MIM: 165500) and autosomal recessive Behr syndrome (MIM: 210000). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with dominant optic atrophy (DOA). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22865259, 25525159, 33841295, 11810270, 34242285) -

OPA1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 09, 2024

Variant summary: OPA1 c.2131C>T (p.Arg711X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251228 control chromosomes (gnomAD). c.2131C>T has been reported in the literature in individuals affected with OPA1-Related Disorders (examples: Delettre_2001, Reis_2013, Li_2017). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11810270, 28081242, 22865259). ClinVar contains an entry for this variant (Variation ID: 216979). Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant optic atrophy classic form Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Oct 30, 2012

- -

OPA1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The OPA1 c.2296C>T variant is predicted to result in premature protein termination (p.Arg766*). This variant, also reported as p.R711*, was previously reported in individuals with autosomal dominant optic atrophy (see, for example, Delettre et al. 2001. PubMed ID: 11810270; Weisschuh et al. 2021. PubMed ID: 34242285). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in OPA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.94
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224906; hg19: chr3-193374986; COSMIC: COSV62482039;