NM_130837.3:c.1148A>G

Variant names:

• chr3-193638064-A-G
• rs398124303
• NM_130837.3:c.1148A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_130837.3(OPA1):​c.1148A>G​(p.Lys383Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K383N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OPA1 NM_130837.3 missense, splice_region
• Scores: Splicing: ADA: 0.9950
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.31
• Publications: 14 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_130837.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 3-193638064-A-G is Pathogenic according to our data. Variant chr3-193638064-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 95733.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.1148A>G	p.Lys383Arg	missense splice_region	Exon 11 of 31	NP_570850.2
	OPA1	NM_130836.3		c.1094A>G	p.Lys365Arg	missense splice_region	Exon 10 of 30	NP_570849.2
	OPA1	NM_130835.3		c.1040A>G	p.Lys347Arg	missense splice_region	Exon 10 of 30	NP_570848.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.1148A>G	p.Lys383Arg	missense splice_region	Exon 11 of 31	ENSP00000355324.2
	OPA1	ENST00000361908.8	TSL:1	c.1094A>G	p.Lys365Arg	missense splice_region	Exon 10 of 30	ENSP00000354681.3
	OPA1	ENST00000361715.6	TSL:5	c.1040A>G	p.Lys347Arg	missense splice_region	Exon 10 of 30	ENSP00000355311.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458436 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725770

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109000

Other (OTH) AF: 0.00 AC: 0 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000308 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RT-PCR analysis demonstrates that c.983 A>G modifies the consensus splice donor site in intron 9 resulting in in-frame skipping of exon 9 (Baris et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14961560, 22857269, 26385429, 25699009, 16418602, 23384603, 30581410, 16735988, 20301426, 22042570, 27535533, 25525159)

Dec 14, 2023

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 328 of the OPA1 protein (p.Lys328Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dominant optic atrophy (PMID: 14961560, 22857269). ClinVar contains an entry for this variant (Variation ID: 95733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 14961560). For these reasons, this variant has been classified as Pathogenic.

Sep 07, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with optic atrophy. Experimental evidence suggests this variant results in abnormal RNA splicing and an in-frame deletion of 38 amino acids from the protein (PMID: 14961560). This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure. Computational tools predict that this variant is damaging.

Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Pathogenic:1

May 23, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (A>G) at position 983 of the coding sequence of the OPA1 gene that results in a lysine to arginine amino acid change at residue 328 of the OPA1 mitochondrial dymin like GTPase protein. Additiolly, this variant falls within the splice donor region for exon 9 and has been experimentally confirmed to result in exon 9 skipping (PMID: 14961560) which disrupts the dymin type G domain of OPA1. This is a previously reported variant (ClinVar 95733) that has been observed in many individuals affected by Autosomal dominant inheritance optic atrophy (PMID: 14961560, 22857269, 25699009 35146926), and segregates with disease in affected families. This variant is absent from the gnomAD population database (0/0 alleles). Multiple bioinformatic tools predict that this Lys to Arg amino acid change would be damaging, and the Lys328 residue at this position is highly conserved across the vertebrate species examined. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BS4, PM2, PP1, PP3, PS3

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Pathogenic:1

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants clustered within the GTPase domain generally develop an optic atrophy syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome or Leigh syndrome, OPA1-related (MONDO#0009723) (PMID: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant lies within the non-canonical splice region of an exon. Analysis of total RNA obtained from an affected individual demonstrated exon skipping, which will result in an in-frame deletion of 38 amino acids (NP_570850.2; p.(Val346_Lys383del)) (PMID: 14961560). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same non-canonical splice site is present in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten families with autosomal dominant optic atrophy (MIM#165500; PMID:22857269), at least one report of optic atrophy plus syndrome (MIM#125250; PMID:29261183); and consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Autosomal dominant optic atrophy classic form Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.51		Gain of glycosylation at S380 (P = 0.0135)
MVP		0.92
MPC		1.4
ClinPred		0.96	D
GERP RS		5.5
PromoterAI		-0.057	Neutral
Varity_R		0.50
gMVP		0.73
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: 1

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

Other links and lift over

dbSNP: rs398124303; hg19: chr3-193355853;