NM_130837.3:c.113_130dupGAAGCATTTATCATTCAC

Variant names:

• chr3-193614797-T-TTTCACGAAGCATTTATCA
• rs863224140
• NM_130837.3:c.113_130dupGAAGCATTTATCATTCAC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_130837.3(OPA1):​c.113_130dupGAAGCATTTATCATTCAC​(p.Arg38_Ser43dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPA1 NM_130837.3 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.827
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_130837.3.
• PP5: Variant 3-193614797-T-TTTCACGAAGCATTTATCA is Pathogenic according to our data. Variant chr3-193614797-T-TTTCACGAAGCATTTATCA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1338854.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.113_130dupGAAGCATTTATCATTCAC	p.Arg38_Ser43dup	disruptive_inframe_insertion	Exon 2 of 31	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.113_130dupGAAGCATTTATCATTCAC	p.Arg38_Ser43dup	disruptive_inframe_insertion	Exon 2 of 31	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tip-toe gait Pathogenic:1

Nov 18, 2021

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83

Splicing

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

Other links and lift over

dbSNP: rs863224140; hg19: chr3-193332586;