VCV000009600.3 - ClinVar

m.3242G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

m.3242G>A

Variation ID: 9600 Accession: VCV000009600.3

Type and length

single nucleotide variant, 1 bp

Location

MT: 3242 (GRCh38) [ NCBI UCSC ] MT: 3242 (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 25, 2016	May 28, 2022	May 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.3242G>A

Protein change

Other names

3242G-A

Canonical SPDI

NC_012920.1:3241:G:A

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: CA280144 OMIM: 590050.0012 dbSNP: rs193303018 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.
Myelodysplastic syndrome	Pathogenic (1)	no assertion criteria provided	Jun 11, 2010	RCV000010223.6
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000850687.2

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 (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: SCV000992918.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (4) PubMed: 31965079‚ 15870203‚ 19460299‚ 22781753 Comment: The NC_012920.1:m.3242G>A variant in MT-TL1 gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the … (more) The NC_012920.1:m.3242G>A variant in MT-TL1 gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PM9, PM10 (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: SCV002517704.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jun 11, 2010)	no assertion criteria provided Method: literature only	MYELODYSPLASTIC SYNDROME, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000030447.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 25, 2016	Publications: PubMed (2) PubMed: 14576046‚ 20550934 Comment on evidence: Ultrastructural abnormalities seen in mitochondria of bone marrow cells of patients with myelodysplastic syndrome (MDS), such as pathologic iron accumulation in the mitochondria of erythroblasts, … (more) Ultrastructural abnormalities seen in mitochondria of bone marrow cells of patients with myelodysplastic syndrome (MDS), such as pathologic iron accumulation in the mitochondria of erythroblasts, suggest that mitochondrial dysfunction may contribute to the pathophysiology of MDS. In a 65-year-old male patient with refractory anemia with excess blasts (RAEB), Gattermann et al. (2004) identified a novel somatic mutation of the mitochondrial MTTL1 gene, 3242G-A. Heteroduplex analysis indicated that 40 to 50% of mitochondrial DNA molecules in the bone marrow carried the mutation. The mutation was not detectable by heteroduplex analysis in the peripheral blood. However, peripheral blood CD34+ cells showed the mutation with a proportion of approximately 50%. In hematopoietic colony assays, CD34+ cells from bone marrow and peripheral blood yielded only colonies with wildtype mtDNA; this result indicated that the mtDNA mutation in CD34+ cells was associated with a maturation defect. Mitochondrial tRNA mutations impair mitochondrial protein synthesis, thereby causing dysfunction of the mitochondrial respiratory chain. Gattermann et al. (2004) suggested that this effect contributed to ineffective hematopoiesis in the patient. Yakubovskaya et al. (2010) found that 3242G interacted with arg251 of MTERF1 (602318) and that the 3242G-A mutation profoundly reduced transcriptional termination by MTERF1. (less)

Comment:

The NC_012920.1:m.3242G>A variant in MT-TL1 gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PM9, PM10

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 DNA m.3242G > A mutation, an under diagnosed cause of hypertrophic cardiomyopathy and renal tubular dysfunction?	Wortmann SB	European journal of medical genetics	2012	PMID: 22781753
Helix unwinding and base flipping enable human MTERF1 to terminate mitochondrial transcription.	Yakubovskaya E	Cell	2010	PMID: 20550934
Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders.	Mimaki M	Mitochondrion	2009	PMID: 19460299
Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease.	Kirino Y	Proceedings of the National Academy of Sciences of the United States of America	2005	PMID: 15870203
Ineffective hematopoiesis linked with a mitochondrial tRNA mutation (G3242A) in a patient with myelodysplastic syndrome.	Gattermann N	Blood	2004	PMID: 14576046

Text-mined citations for rs193303018 ...

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 Dec 11, 2022

ClinVar Genomic variation as it relates to human health

m.3242G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs193303018 ...