rs104893753

Positions:

• chr3-193643005-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.1261C>T​(p.Arg421*) 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 1,461,602 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R421R) has been classified as Benign. 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 criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.04

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 (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 3-193643005-C-T is Pathogenic according to our data. Variant chr3-193643005-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193643005-C-T is described in Lovd as [Pathogenic]. Variant chr3-193643005-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1261C>T	p.Arg421*	stop_gained	13/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1261C>T	p.Arg421*	stop_gained	13/31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461602 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

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

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5085). This variant is also known as c.1261C>T (p.Arg421*). This premature translational stop signal has been observed in individual(s) with OPA1-related conditions (PMID: 11440988, 33841295). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg366*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -

Autosomal dominant optic atrophy classic form Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed stop gained c.1261C>T(p.Arg421Ter) variant in OPA1 gene has been reported previously in heterozygous state in multiple individuals affected with optic atrophy (Charif M, et al., 2021; Pesch UE, et al., 2001; Alexander C, et al., 2000). The c.1261C>T variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). The nucleotide change c.1261C>T in OPA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (MutationTaster - Disease causing) predicts a damaging effect on protein structure and function for this variant. This sequence change creates a premature translational stop signal (p.Arg366Ter) in the OPA1 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in OPA1 gene have been previously reported to be pathogenic (Yu-Wai-Man P, et al., 2011). For these reasons, this variant has been classified as Pathogenic. -

Optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2021

- -

OPA1-related optic atrophy with or without extraocular features Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous p.Arg403Ter variant in OPA1 was identified by our study in one individual with optic atrophy. The p.Arg403Ter variant in OPA1 has been previously reported in 10 unrelated individuals with autosomal dominant OPA1-related optic atrophy with or without extraocular features (PMID: 34242285, PMID: 24369534, PMID: 12842213, PMID: 11810270, PMID: 14961560, PMID: 11017080, PMID: 33841295) and segregated with disease in 4 affected relatives from one family (PMID: 11017080). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 5085) and has been interpreted as pathogenic by OMIM, Invitae, Eurofins NTD LLC, and CeGaT Center for Human Genetics Tuebingen. This variant was absent from large population studies. RT-PCR analysis of affected tissue showed evidence of reduced transcript expression versus wild-type (PMID: 17722006). This nonsense variant leads to a premature termination codon at position 403, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the OPA1 gene is an established disease mechanism in autosomal dominant OPA1-related optic atrophy with or without extraocular features. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant OPA1-related optic atrophy with or without extraocular features. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PP1, PS3_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.93
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104893753; hg19: chr3-193360794; COSMIC: COSV62483194; COSMIC: COSV62483194;