3-193631620-CAA-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_130837.3(OPA1):c.800_801del(p.Lys267ArgfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
OPA1
NM_130837.3 frameshift
NM_130837.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.95
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]
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ACMG classification
Classification made for transcript
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 3-193631620-CAA-C is Pathogenic according to our data. Variant chr3-193631620-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 198219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193631620-CAA-C is described in Lovd as [Pathogenic]. Variant chr3-193631620-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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OPA1 | NM_130837.3 | c.800_801del | p.Lys267ArgfsTer4 | frameshift_variant | 8/31 | ENST00000361510.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OPA1 | ENST00000361510.8 | c.800_801del | p.Lys267ArgfsTer4 | frameshift_variant | 8/31 | 5 | NM_130837.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250910Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135722
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457664Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 725462
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74270
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2023 | Frameshift 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 at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20639189, 11440989, 28005958, 16158427, 20417570, 20157015, 33841295, 32488064, 33084218, 34242285, 23384603) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change creates a premature translational stop signal (p.Lys212Argfs*4) 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 present in population databases (rs778041035, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with OPA1-related conditions (PMID: 11440989, 28005958). This variant is also known as 635del(AA) or c.800_801delAA p.K267Rfs*4. ClinVar contains an entry for this variant (Variation ID: 198219). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 08, 2022 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with optic atrophy. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2022 | The c.635_636delAA (p.K212Rfs*4) alteration, located in exon 6 (coding exon 6) of the OPA1 gene, consists of a deletion of 2 nucleotides from position 635 to 636, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ Based on the available evidence, the OPA1 c.635_636delAA (p.K212Rfs*4) alteration is classified as pathogenic for autosomal dominant OPA1-related optic atrophy and autosomal recessive Behr syndrome; however, the association of this alteration with autosomal dominant OPA1-related optic atrophy plus syndrome is unknown. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). The alteration has been previously observed in multiple affected individuals with features of various OPA1-related disorders (Toomes, 2001;Yu-Wai-Man, 2010; Castro-Miro, 2016; Salinas, 2020; Weisschuh, 2021). Based on the available evidence, this alteration is classified as pathogenic. - |
Autosomal dominant optic atrophy classic form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 29, 2021 | - - |
Stargardt disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DBGen Ocular Genomics | Jan 01, 2022 | Class 5 ACMG Guidelines, 2015 (PMID:25741868) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at