VCV000689871.3 - ClinVar

NC_012920.1(MT-TL1):m.3302A>G

Germline

Top reviewed classifications are shown here.

Submission summary:

5 submissions

4 submitters

4 conditions

Reviewed by expert panel

Likely pathogenic

Nov 2022 by ClinGen Mitoch… FDA Recognized Database

for Mitochondrial disease

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_012920.1(MT-TL1):m.3302A>G

Variation ID: 689871 Accession: VCV000689871.3

Type and length

single nucleotide variant, 1 bp

Location

MT: 3302 (GRCh38) [ NCBI UCSC ] MT: 3302 (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	Sep 22, 2019	May 19, 2024	Nov 14, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.3302A>G

Protein change

Other names

3302A-G

Canonical SPDI

NC_012920.1:3301:A:G

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

Genetic Testing Registry (GTR): GTR000591967 Genetic Testing Registry (GTR): GTR000591975 Genetic Testing Registry (GTR): GTR000591976 OMIM: 590050.0013 dbSNP: rs1603218878 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-TL1		-	-	GRCh38	37	39

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.
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000850712.2
Mitochondrial disease	Likely pathogenic (1)	reviewed by expert panel	Nov 14, 2022	RCV003153873.1
MITOCHONDRIAL SKELETAL MYOPATHY	Pathogenic (1)	no assertion criteria provided	May 15, 2024	RCV004555600.1
MITOCHONDRIAL CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY	Pathogenic (1)	no assertion criteria provided	May 15, 2024	RCV004555599.1

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 (Nov 14, 2022)	reviewed by expert panel (McCormick et al. (Hum Mutat. 2020)) 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: SCV003842287.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ea99d7f0-a9b4-4d52-be0e-7f3f093e0831 Comment: The m.3302A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with MELAS and the … (more) The m.3302A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with MELAS and the fourth had myopathy and respiratory failure. The heteroplasmy levels of the variant in affected individuals ranged from 45% to homoplasmic (PS4_moderate; PMIDs: 19370763, 8366098). This variant segregated with disease in one family as the proband and his mother harbored the variant at high heteroplasmy levels (values not provided) in fibroblasts and the variant was homoplasmic in muscle in the proband. An unaffected maternal aunt did not harbor the variant in her white blood cells (PP1; PMID: 8366098). There are no reports of de novo occurrences to our knowledge. Cybrid studies supported the functional impact of this variant as cybrids with the variant present at 98% heteroplasmy had a 6-fold reduction of respiration compared to those with 77% heteroplasmy showing no respiration defect (PS3_supporting; PMID: 17130166). The computational predictor MitoTIP suggests this variant is pathogenic (85.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PP3. (less)
Pathogenic (Jul 12, 2019)	criteria provided, single submitter (Modified ACMG Guidelines (Unpublished)) Method: clinical testing	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV000992945.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (3) PubMed: 31965079‚ 8366098‚ 7635294 Comment: The NC_012920.1:m.3302A>G variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following … (more) The NC_012920.1:m.3302A>G variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517713.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (May 15, 2024)	no assertion criteria provided Method: literature only	MITOCHONDRIAL SKELETAL MYOPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV005044061.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Publications: PubMed (2) PubMed: 8366098‚ 28716227 Comment on evidence: In a woman with mitochondrial skeletal myopathy, Bindoff et al. (1993) identified a c.3302A-G transition in the MTTL1 gene. The mutation, which was identified by … (more) In a woman with mitochondrial skeletal myopathy, Bindoff et al. (1993) identified a c.3302A-G transition in the MTTL1 gene. The mutation, which was identified by PCR, sequencing, and restriction analysis, was also present in the patient's mother. The mutation was present at levels close to homoplasmy in the patient's muscle tissue and was heteroplasmic in fibroblasts from the patient and in white blood cells from the patient and her mother. In a 16-year-old boy (P10) with mitochondrial myopathy, Lu et al. (2017) identified a c.3302A-G mutation in the MTTL1 gene. The mutation was identified by Sanger sequencing of the mitochondrial genome. Mutation heteroplasmy was not reported. Ragged-red fibers and COX-negative fibers were identified in a muscle specimen from the patient. In a patient with dilated cardiomyopathy, et al. (2022) identified a c.3302A-G mutation in the MTTL1 gene. The mutation was identified by sequencing of the mitochondrial tRNAs in peripheral blood. The mutation was not preset in 200 healthy controls. (less)
Pathogenic (May 15, 2024)	no assertion criteria provided Method: literature only	MITOCHONDRIAL CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV005044062.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Publications: PubMed (2) PubMed: 8366098‚ 28716227 Comment on evidence: In a woman with mitochondrial skeletal myopathy, Bindoff et al. (1993) identified a c.3302A-G transition in the MTTL1 gene. The mutation, which was identified by … (more) In a woman with mitochondrial skeletal myopathy, Bindoff et al. (1993) identified a c.3302A-G transition in the MTTL1 gene. The mutation, which was identified by PCR, sequencing, and restriction analysis, was also present in the patient's mother. The mutation was present at levels close to homoplasmy in the patient's muscle tissue and was heteroplasmic in fibroblasts from the patient and in white blood cells from the patient and her mother. In a 16-year-old boy (P10) with mitochondrial myopathy, Lu et al. (2017) identified a c.3302A-G mutation in the MTTL1 gene. The mutation was identified by Sanger sequencing of the mitochondrial genome. Mutation heteroplasmy was not reported. Ragged-red fibers and COX-negative fibers were identified in a muscle specimen from the patient. In a patient with dilated cardiomyopathy, et al. (2022) identified a c.3302A-G mutation in the MTTL1 gene. The mutation was identified by sequencing of the mitochondrial tRNAs in peripheral blood. The mutation was not preset in 200 healthy controls. (less)

Comment:

The m.3302A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with MELAS and the fourth had myopathy and respiratory failure. The heteroplasmy levels of the variant in affected individuals ranged from 45% to homoplasmic (PS4_moderate; PMIDs: 19370763, 8366098). This variant segregated with disease in one family as the proband and his mother harbored the variant at high heteroplasmy levels (values not provided) in fibroblasts and the variant was homoplasmic in muscle in the proband. An unaffected maternal aunt did not harbor the variant in her white blood cells (PP1; PMID: 8366098). There are no reports of de novo occurrences to our knowledge. Cybrid studies supported the functional impact of this variant as cybrids with the variant present at 98% heteroplasmy had a 6-fold reduction of respiration compared to those with 77% heteroplasmy showing no respiration defect (PS3_supporting; PMID: 17130166). The computational predictor MitoTIP suggests this variant is pathogenic (85.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PP3.

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
Interpretation of mitochondrial tRNA variants.	Wong LC	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31965079
Mitochondrial tRNA genes are hotspots for mutations in a cohort of patients with exercise intolerance and mitochondrial myopathy.	Lu Y	Journal of the neurological sciences	2017	PMID: 28716227
Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.	Howell N	Genetics	1995	PMID: 7635294
Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism.	Bindoff LA	The Journal of biological chemistry	1993	PMID: 8366098
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ea99d7f0-a9b4-4d52-be0e-7f3f093e0831	-	-	-	-

Text-mined citations for rs1603218878 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 27, 2024

ClinVar Genomic variation as it relates to human health

NC_012920.1(MT-TL1):m.3302A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1603218878 ...