VCV000009731.2 - ClinVar

NC_012920.1(MT-ND1):m.3902_3908inv

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely pathogenic

for Mitochondrial disease

Classification is based on the expert panel submission

Jun 2022 by ClinGen Mitochondrial Disease Nuclear and Mitochondrial Va…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_012920.1(MT-ND1):m.3902_3908inv

Variation ID: 9731 Accession: VCV000009731.2

Type and length

Inversion, 7 bp

Location

MT: 3902-3908 (GRCh38) [ NCBI UCSC ] MT: 3902-3908 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 16, 2018	Jul 9, 2022	Jun 30, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.3902_3908inv

Protein change

Other names

m.3902_3908invACCTTGC

Canonical SPDI

NC_012920.1:3901:ACCTTGC:GCAAGGT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA082749 Genetic Testing Registry (GTR): GTR000591967 Genetic Testing Registry (GTR): GTR000591975 Genetic Testing Registry (GTR): GTR000591976 OMIM: 516000.0009 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MT-ND1		-	-	GRCh38	182	186

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3	Pathogenic (1)	no assertion criteria provided	Mar 1, 2006	RCV000010383.5
Mitochondrial disease	Likely pathogenic (1)	reviewed by expert panel	Jun 30, 2022	RCV002260595.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jun 30, 2022) C Contributing to aggregate classification	reviewed by expert panel (clingen mito disease acmg specifications v1-1) Method: curation	Mitochondrial disease (Mitochondrial inheritance) Affected status: unknown Allele origin: germline	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV002540734.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b04011ab-11a2-4533-99f7-2507ea2fd88b Comment: The m.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical … (more) The m.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical features including myopathy, exercise intolerance, Leigh syndrome, cardiomyopathy, failure to thrive, lactic acidosis, nephropathy, sensorineural hearing loss, and diabetes mellitus (PS4_moderate; PMIDs: 10775530, 16492986, 27290639, 34135385). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are at least three de novo occurrences reported in the literature and this variant in the case reported by the expert panel member also occurred de novo (PM6_strong; PMIDs: 16492986, 10775530, 27290639). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). E. coli models demonstrated two different functional defects, reduced complex activity and reduced proton translocation (PS3_moderate; PMIDs; 34135385, 35234296). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 9, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PS3_moderate. (less)
Pathogenic (Mar 01, 2006) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030609.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 16, 2018	Publications: PubMed (3) PubMed: 10775530‚ 2125637‚ 16492986 Comment on evidence: Musumeci et al. (2000) studied a 43-year-old man, originally reported by Bet et al. (1990), who had complained, since childhood, of severe exercise intolerance and … (more) Musumeci et al. (2000) studied a 43-year-old man, originally reported by Bet et al. (1990), who had complained, since childhood, of severe exercise intolerance and myalgia. Morphologic and biochemical studies of muscles showed 40% ragged-red fibers and an approximately 40% reduction of complex I activity consistent with complex I deficiency (MC1DM3). At age 43 years, he still complained of exercise intolerance; neurologic examination showed mild proximal limb weakness but was otherwise normal. His family history was noncontributory. The mother was alive and had always been a very active person. Neither of his 2 sibs complained of exercise intolerance. Musumeci et al. (2000) found an inversion of 7 nucleotides within the ND1 gene, which maintained the reading frame. The inversion, which altered 3 highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This was said to be the first report of a pathogenic inversion mutation in human mtDNA. The inversion changed the normal amino acids 199-201 from asp-leu-ala to gly-lys-val. The 7-bp inverted segment was flanked by 8-bp inverted repeats. Blakely et al. (2006) reported a female infant with the same 7-bp inversion in the MTND1 gene described by Musumeci et al. (2000). However, the infant had a much more severe phenotype and died at age 1 month with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis. The mutation was present at high levels in several tissues including the heart (85%), muscle (84%), liver (87%), and cultured skin fibroblasts (70%). Complex I activity was estimated to be 24% of control values. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Blakely et al. (2006) noted that their findings illustrated the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasized the need for appropriate genetic counseling for families affected by mtDNA disease. (less)

Comment:

The m.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical features including myopathy, exercise intolerance, Leigh syndrome, cardiomyopathy, failure to thrive, lactic acidosis, nephropathy, sensorineural hearing loss, and diabetes mellitus (PS4_moderate; PMIDs: 10775530, 16492986, 27290639, 34135385). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are at least three de novo occurrences reported in the literature and this variant in the case reported by the expert panel member also occurred de novo (PM6_strong; PMIDs: 16492986, 10775530, 27290639). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). E. coli models demonstrated two different functional defects, reduced complex activity and reduced proton translocation (PS3_moderate; PMIDs; 34135385, 35234296). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 9, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PS3_moderate.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.	Blakely EL	Pediatric research	2006	PMID: 16492986
Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy.	Musumeci O	American journal of human genetics	2000	PMID: 10775530
A case of mitochondrial myopathy, lactic acidosis and complex I deficiency.	Bet L	Journal of neurology	1990	PMID: 2125637
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b04011ab-11a2-4533-99f7-2507ea2fd88b	-	-	-	-

Text-mined citations for this variant ...

Record last updated Dec 09, 2023

ClinVar Genomic variation as it relates to human health

NC_012920.1(MT-ND1):m.3902_3908inv

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...