rs80356530

Variant names:

• chr3-193667167-CAGTT-C
• rs80356530
• NM_130837.3:c.2873_2876delTTAG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PP3_Moderate PP5_Very_Strong

The NM_130837.3(OPA1):​c.2873_2876delTTAG​(p.Val958fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,453,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005398583: "This variant has strong functional evidence supporting abnormal protein function. Skin fibroblasts from affected individuals heterozygous for this variant demonstrated reduced OPA1 protein levels and abnormal mitochondrial morphology and fusion compared to control fibroblasts (PMID:18222991)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V958V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: OPA1 NM_130837.3 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32 O:2
• Conservation: PhyloP100: 9.95
• Publications: 55 publications found

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]

OPA1 Gene-Disease associations (from GenCC):

• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• optic atrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• OPA1-related optic atrophy with or without extraocular features

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Behr syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal dominant optic atrophy plus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306963 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005398583: "This variant has strong functional evidence supporting abnormal protein function. Skin fibroblasts from affected individuals heterozygous for this variant demonstrated reduced OPA1 protein levels and abnormal mitochondrial morphology and fusion compared to control fibroblasts (PMID: 18222991)."; SCV000614384: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18222991); SCV005061372: The variant showed it was more prone to cell death than controls after an exogenous oxidative stress in fibroblasts (Zanna_2008).; SCV006384199: An animal model expressing this variant exhibited phenotype(s) consistent with OPA1-related disease (Sarzi, 2012; Affortit, 2024).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-193667167-CAGTT-C is Pathogenic according to our data. Variant chr3-193667167-CAGTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130837.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.2873_2876delTTAG	p.Val958fs	frameshift splice_region	Exon 29 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.2819_2822delTTAG	p.Val940fs	frameshift splice_region	Exon 28 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.2765_2768delTTAG	p.Val922fs	frameshift splice_region	Exon 28 of 30	NP_570848.1	E5KLJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.2873_2876delTTAG	p.Val958fs	frameshift splice_region	Exon 29 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.2819_2822delTTAG	p.Val940fs	frameshift splice_region	Exon 28 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.2888_2891delTTAG	p.Val963fs	frameshift splice_region	Exon 30 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251242 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 32 AN: 1301222 Hom.: 0 AF XY: 0.0000229 AC XY: 15 AN XY: 656424

African (AFR) AF: 0.0000329 AC: 1 AN: 30400

American (AMR) AF: 0.0000225 AC: 1 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38940

South Asian (SAS) AF: 0.0000361 AC: 3 AN: 83042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 0.0000259 AC: 25 AN: 965470

Other (OTH) AF: 0.0000182 AC: 1 AN: 54918

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74256

African (AFR) AF: 0.0000725 AC: 3 AN: 41376

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Autosomal dominant optic atrophy classic form (12)
10	-	-	not provided (10)
2	-	-	OPA1-related disorder (2)
1	-	-	3-Methylglutaconic aciduria type 3 (1)
1	-	-	Abortive cerebellar ataxia (1)
1	-	-	Abortive cerebellar ataxia;C0338508:Autosomal dominant optic atrophy classic form;C1847730:Glaucoma, normal tension, susceptibility to;C3276549:Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;C4225163:Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Optic atrophy (1)
1	-	-	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1)
1	-	-	Retinal dystrophy (1)
1	-	-	See cases (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 7
DS_AL_spliceai		0.98		Position offset: 3

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

Other links and lift over

dbSNP: rs80356530; hg19: chr3-193384956;