3-193647110-C-A

Position:

• chr3-193647110-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_130837.3(OPA1):​c.1800C>A​(p.Ser600Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.618

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_130837.3 (OPA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 3-193647110-C-A is Pathogenic according to our data. Variant chr3-193647110-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 95712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193647110-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1800C>A	p.Ser600Arg	missense_variant	19/31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1800C>A	p.Ser600Arg	missense_variant	19/31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	Identified in patients with features of OPA1-related optic atrophy spectrum disorder referred for genetic testing at GeneDx and in published literature (Yu-Wai-Man et al., 2011; Nakamura et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29034899, 16513463, 23384603, 32025183, 20952381, 20185555, 22433900, 18158317, 18065439) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2012	- -

OPA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The OPA1 c.1800C>A variant is predicted to result in the amino acid substitution p.Ser600Arg. This variant has been reported in the heterozygous state in multiple unrelated individuals with optic atrophy (denoted as c.1635C>A [p.S545R] using alternate transcript NM_015560.2 in Nakamura et al. 2006. PubMed ID: 16513463; Yu-Wai-Man et al. 2011. PubMed ID: 20952381). An alternate variant (c.1800C>G) causing the same amino acid substitution has also been reported in individuals with optic atrophy (Amati-Bonneau et al. 2007. PubMed ID: 18158317; Hudson et al. 2008. PubMed ID: 18065439). This variant has not been documented in a large population database, indicating this variant is rare. Given the evidence, we interpret c.1800C>A (p.Ser600Arg) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;D;D;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.8	.;.;.;L;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D;D;D;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;D;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.;.;.;.
Vest4		0.94
MutPred		0.76		.;.;Gain of MoRF binding (P = 0.0204);.;.;.;.;.;.;.;.;
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.95

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: rs398124298; hg19: chr3-193364899;