VCV000030004.3 - ClinVar

m.12201T>C

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

3 conditions

Reviewed by expert panel

Likely pathogenic

Apr 2023 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.12201T>C

Variation ID: 30004 Accession: VCV000030004.3

Type and length

single nucleotide variant, 1 bp

Location

MT: 12201 (GRCh38) [ NCBI UCSC ] MT: 12201 (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	Aug 5, 2023	Apr 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.12201T>C

Protein change

Other names

12201T-C

Canonical SPDI

NC_012920.1:12200:T:C

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: CA259740 OMIM: 590040.0004 dbSNP: rs387906733 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-TH		-	-	GRCh38	40	57

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 non-syndromic sensorineural hearing loss	Pathogenic (1)	no assertion criteria provided	Oct 1, 2011	RCV000022899.2
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	Uncertain significance (1)	criteria provided, single submitter	Jul 12, 2019	RCV000851039.1
Mitochondrial disease	Likely pathogenic (1)	reviewed by expert panel	Apr 17, 2023	RCV003319172.1

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 (Apr 17, 2023)	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: SCV004023278.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6c102897-0080-4a7d-a221-5b0063f8108a Comment: The m.12201T>C variant in MT-TH has been reported in three families with features of primary mitochondrial disease (PS4_supporting). The first family reported was 5-generation Han … (more) The m.12201T>C variant in MT-TH has been reported in three families with features of primary mitochondrial disease (PS4_supporting). The first family reported was 5-generation Han Chinese family with late-onset non-syndromic deafness (PMIDs: 21931169, 24920829, 31819004, 32169613). A second case was reported in a Vietnamese cohort of children with non-syndromic hearing loss (https://www.ojhas.org/issue65/2018-1-6.html). The third case was reported in a cohort of individuals with dilated cardiomyopathy (PMID: 34991096). Seventeen of 35 matrilineal relatives in the first reported family exhibited variable severity and age at onset of sensorineural hearing loss and blood heteroplasmy levels correlated with both onset age and symptom severity (PP1_moderate). There are no reported de novo occurrences of this variant to our knowledge. Although there are several occurrences in population databases, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (67th percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). Cybrid studies show different classes of function defects including a decrease in the steady-state level of tRNAHis, diminished respiratory capacity, marked decreases in mtATP levels and membrane potential, increased reactive oxygen species (ROS) production, decreased melting temperature, conformational changes, and instability of the mutated tRNA, and HARS2 overexpression corrected the mitochondrial dysfunction (PS3_moderate; PMIDs: 24920829, 31819004). 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 April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_moderate. (less)
Uncertain significance (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: SCV000993273.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (1) PubMed: 31965079 Comment: The NC_012920.1:m.12201T>C variant in MT-TH gene is interpreted to be a Unknown Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the … (more) The NC_012920.1:m.12201T>C variant in MT-TH gene is interpreted to be a Unknown Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PP3, BP6 (less)
Pathogenic (Oct 01, 2011)	no assertion criteria provided Method: literature only	DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044190.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 21931169 Comment on evidence: In affected members of a large 5-generation Han Chinese family with maternally inherited nonsyndromic adult-onset hearing loss (500008), Yan et al. (2011) identified a heteroplasmic … (more) In affected members of a large 5-generation Han Chinese family with maternally inherited nonsyndromic adult-onset hearing loss (500008), Yan et al. (2011) identified a heteroplasmic 12201T-C transition in the MTTH gene, affecting the acceptor stem of tRNA-His. The mutation was not found in 342 Han Chinese controls. There was wide variability in age at onset and severity, which correlated with mutation load, but the average age at onset was 29 years. Lymphoblastoid cell lines from 3 mutation carriers showed decreased levels of MTTH mRNA (about 25% of normal) as well as about 50% reduction in mitochondrial translation products compared to controls. Overall oxygen consumption of these cells was about 65% of normal, indicating defective respiration. (less)

Comment:

The m.12201T>C variant in MT-TH has been reported in three families with features of primary mitochondrial disease (PS4_supporting). The first family reported was 5-generation Han Chinese family with late-onset non-syndromic deafness (PMIDs: 21931169, 24920829, 31819004, 32169613). A second case was reported in a Vietnamese cohort of children with non-syndromic hearing loss (https://www.ojhas.org/issue65/2018-1-6.html). The third case was reported in a cohort of individuals with dilated cardiomyopathy (PMID: 34991096). Seventeen of 35 matrilineal relatives in the first reported family exhibited variable severity and age at onset of sensorineural hearing loss and blood heteroplasmy levels correlated with both onset age and symptom severity (PP1_moderate). There are no reported de novo occurrences of this variant to our knowledge. Although there are several occurrences in population databases, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (67th percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). Cybrid studies show different classes of function defects including a decrease in the steady-state level of tRNAHis, diminished respiratory capacity, marked decreases in mtATP levels and membrane potential, increased reactive oxygen species (ROS) production, decreased melting temperature, conformational changes, and instability of the mutated tRNA, and HARS2 overexpression corrected the mitochondrial dysfunction (PS3_moderate; PMIDs: 24920829, 31819004). 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 April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, 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
Interpretation of mitochondrial tRNA variants.	Wong LC	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31965079
Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene.	Yan X	Journal of medical genetics	2011	PMID: 21931169
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6c102897-0080-4a7d-a221-5b0063f8108a	-	-	-	-

Text-mined citations for rs387906733 ...

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 09, 2023

ClinVar Genomic variation as it relates to human health

m.12201T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906733 ...