VCV000009595.3 - ClinVar

m.3251A>G

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

m.3251A>G

Variation ID: 9595 Accession: VCV000009595.3

Type and length

single nucleotide variant, 1 bp

Location

MT: 3251 (GRCh38) [ NCBI UCSC ] MT: 3251 (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	Apr 4, 2013	May 28, 2022	May 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.3251A>G

Protein change

Other names

3251A-G

Canonical SPDI

NC_012920.1:3250: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

ClinGen: CA120565 OMIM: 590050.0006 dbSNP: rs199474662 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.
Progressive external ophthalmoplegia, proximal myopathy, and sudden death	Pathogenic (1)	no assertion criteria provided	Mar 1, 1996	RCV000010218.2
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000850691.2

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.
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: SCV002517707.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
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: SCV000992923.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (3) PubMed: 31965079‚ 8265770‚ 8786060 Comment: The NC_012920.1:m.3251A>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.3251A>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, PM8, PM9, PP4, PP6 (less)
Pathogenic (Mar 01, 1996)	no assertion criteria provided Method: literature only	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, PROXIMAL MYOPATHY, AND SUDDEN DEATH Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030442.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 8265770‚ 8786060 Comment on evidence: Sweeney et al. (1993) reported a family exhibiting maternal inheritance of a variable syndrome comprising ocular, neck, and proximal upper limb weakness, psychiatric features, and … (more) Sweeney et al. (1993) reported a family exhibiting maternal inheritance of a variable syndrome comprising ocular, neck, and proximal upper limb weakness, psychiatric features, and sudden death. Of 15 definitely or probably affected individuals, 7 had died in early adult life, probably of respiratory failure. All living affected members of the family showed an A-to-G transition at nucleotide 3251 of the MTTL1 gene. In a girl who died at age 14 from a rapidly progressive mitochondrial myopathy, Houshmand et al. (1996) found heteroplasmy for the A3251G mutation. A large proportion of muscle fibers contained accumulations of abnormal mitochondria but no cytochrome c oxidase deficient fibers were present. Studies of isolated muscle mitochondria revealed a profound isolated complex I deficiency. A high percentage of mutant mtDNA was found in muscle (94%), fibroblasts (93%), brain (90%), liver (80%), and heart (79%). The family was not available for investigation. The proportion of mutant mtDNA was 28% in normal-appearing fibers and 61% in abnormal fibers. The patient had been healthy until age 10 years when she had insidious onset of gastrointestinal symptoms with diarrhea, nausea, fatigue, and tachycardia on mild physical exertion. Terminally, in the last years of life she developed persistent tachycardia, lactic acidosis, and hypercapnia, and in the last month of life, cardiorespiratory failure. (less)

Comment:

The NC_012920.1:m.3251A>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, PM8, PM9, PP4, PP6

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
Fatal mitochondrial myopathy, lactic acidosis, and complex I deficiency associated with a heteroplasmic A --> G mutation at position 3251 in the mitochondrial tRNALeu(UUR) gne.	Houshmand M	Human genetics	1996	PMID: 8786060
Mitochondrial myopathy associated with sudden death in young adults and a novel mutation in the mitochondrial DNA leucine transfer RNA(UUR) gene.	Sweeney MG	The Quarterly journal of medicine	1993	PMID: 8265770

Text-mined citations for rs199474662 ...

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 Apr 23, 2023

ClinVar Genomic variation as it relates to human health

m.3251A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199474662 ...