VCV000009606.4 - ClinVar

m.4300A>G

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

4 conditions

Reviewed by expert panel

Likely pathogenic

Sep 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

m.4300A>G

Variation ID: 9606 Accession: VCV000009606.4

Type and length

single nucleotide variant, 1 bp

Location

MT: 4300 (GRCh38) [ NCBI UCSC ] MT: 4300 (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	Oct 15, 2022	Sep 12, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.4300A>G

Protein change

Other names

4300A-G

Canonical SPDI

NC_012920.1:4299: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: CA254842 Genetic Testing Registry (GTR): GTR000591967 Genetic Testing Registry (GTR): GTR000591969 Genetic Testing Registry (GTR): GTR000591975 Genetic Testing Registry (GTR): GTR000591976 OMIM: 590045.0006 dbSNP: rs121434470 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-TI		-	-	GRCh38	27	29

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.
Primary familial hypertrophic cardiomyopathy	Pathogenic (1)	no assertion criteria provided	May 21, 2003	RCV000010229.2
Asymmetric septal hypertrophy Primary dilated cardiomyopathy	Likely pathogenic (1)	no assertion criteria provided	Jan 1, 2018	RCV001251031.1
MERRF syndrome	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247293.1
Mitochondrial disease	Likely pathogenic (1)	reviewed by expert panel	Sep 12, 2022	RCV002291210.1

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 (Sep 12, 2022)	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: SCV002583532.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8147d0ba-1ed5-4fe0-94d1-df5fbb857a6c Comment: The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of … (more) The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID: 1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for PM2_supporting. There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_moderate. (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	MERRF syndrome Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517699.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (May 21, 2003)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030453.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 12767666 Comment on evidence: In 2 families with hypertrophic cardiomyopathy (see 192600), Taylor et al. (2003) identified a homoplasmic 4300G-A transition in the MTTI gene. Cardiac tissue from the … (more) In 2 families with hypertrophic cardiomyopathy (see 192600), Taylor et al. (2003) identified a homoplasmic 4300G-A transition in the MTTI gene. Cardiac tissue from the proband in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of skeletal muscle were normal. The mutation was present in all samples from affected individuals and other maternal relatives. Taylor et al. (2003) stated that this was the first report of a homoplasmic mitochondrial tRNA mutation causing maternally inherited hypertrophic cardiomyopathy, and noted that these cases confirm the importance of the MTTI gene as a hotspot for mitochondrial cardiomyopathy mutations. (less)
Likely pathogenic (Jan 01, 2018)	no assertion criteria provided Method: research	Asymmetric septal hypertrophy Primary dilated cardiomyopathy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001426424.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020

Comment:

The m.4300A>G variant in MT-TI has been reported in at least 17 individuals from eight families with hypertrophic cardiomyopathy. Affected individuals had variable ages of onset (11 months old to 40s). All cases developed hypertrophic cardiomyopathy. Muscle biopsy revealed COX negative fibers in cardiac tissue and one case had ragged red fibers in skeletal muscle. Heteroplasmy levels were predominantly the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Other affected family members did harbor the variant at 60-100%. Of note, some healthy family members had the variant ranging from 40-100% (PS4_moderate; PMIDs: 10065021, 7646516, 12767666, 12711217, 23847141). This variant segregated with disease in a family with LVH with diffuse hypertrophy as the proband's heteroplasmy was 98% in heart, 85% in muscle, and 95% in blood. His seven affected maternal relatives had heteroplasmy levels ranging from 60-92% in blood. His 12 unaffected relatives available for testing heteroplasmy ranged 50-78% in blood (PP1_moderate, PMID: 1006502). There are no reported de novo occurrences of this variant to our knowledge. There are three occurrences of this variant in Helix dataset (frequency of 0.001%) that includes two homoplasmic and one heteroplasmic individuals. This variant is absent in gnomAD v3.1.2 and in GenBank dataset therefore the frequency is still low enough to meet criteria for PM2_supporting. There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is pathogenic (79.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). 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 September 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PP1_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
A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy.	Taylor RW	Journal of the American College of Cardiology	2003	PMID: 12767666
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8147d0ba-1ed5-4fe0-94d1-df5fbb857a6c	-	-	-	-

Text-mined citations for rs121434470 ...

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 06, 2024

ClinVar Genomic variation as it relates to human health

m.4300A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434470 ...