VCV000009609.2 - ClinVar

NC_012920.1(MT-TH):m.12183G>A

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

2 conditions

Reviewed by expert panel

Uncertain Significance

Mar 2024 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-TH):m.12183G>A

Variation ID: 9609 Accession: VCV000009609.2

Type and length

single nucleotide variant, 1 bp

Location

MT: 12183 (GRCh38) [ NCBI UCSC ] MT: 12183 (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	Nov 22, 2014	Aug 18, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.12183G>A

Protein change

Other names

12183G-A

Canonical SPDI

NC_012920.1:12182: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: CA120575 OMIM: 590040.0002 dbSNP: rs121434473 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.
Pigmentary retinopathy and sensorineural deafness	Pathogenic (1)	no assertion criteria provided	Apr 8, 2003	RCV000010233.5
Mitochondrial disease	Uncertain significance (1)	reviewed by expert panel	Mar 26, 2024	RCV004691089.1

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.
Uncertain Significance (Mar 26, 2024)	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: SCV005187331.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Publications: PubMed (1) PubMed: 12682337 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f424889b-44a5-4540-829b-c8e5a20d42a7 Comment: The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, … (more) The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood. This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337). There are no reported de novo occurrences to our knowledge. There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337). The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PM2_supporting, PS3_supporting, PP3. (less)
Pathogenic (Apr 08, 2003)	no assertion criteria provided Method: literature only	PIGMENTARY RETINOPATHY AND SENSORINEURAL DEAFNESS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030457.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 22, 2014	Publications: PubMed (1) PubMed: 12682337 Comment on evidence: In a male patient with pigmentary retinopathy with visual loss, bilateral sensorineural deafness, muscle hypotrophy, testicular dysfunction, and ataxia, Crimi et al. (2003) identified a … (more) In a male patient with pigmentary retinopathy with visual loss, bilateral sensorineural deafness, muscle hypotrophy, testicular dysfunction, and ataxia, Crimi et al. (2003) identified a heteroplasmic 12183G-A mutation in the MTTH gene. The mutation occurred in a highly conserved region of the T-psi-C stem of the tRNA. The clinical course was progressive, with visual loss beginning at age 7 years, hearing loss at age 11 years, and muscle weakness, ataxia, dysarthria, and testicular dysfunction apparent by age 20 years. Brain imaging showed cerebellar hypotrophy and bilateral basal ganglia calcifications. The patient's sister had retinopathy and sensorineural hypoacusis, whereas their mother had bilateral cataracts and audiometric defects; both also carried the 12183G-A mutation. Crimi et al. (2003) noted that the gradient of clinical severity reflected the degree of mutation heteroplasmy. (less)

Comment:

The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood. This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337). There are no reported de novo occurrences to our knowledge. There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337). The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PM2_supporting, PS3_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
A mitochondrial tRNA(His) gene mutation causing pigmentary retinopathy and neurosensorial deafness.	Crimi M	Neurology	2003	PMID: 12682337
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f424889b-44a5-4540-829b-c8e5a20d42a7	-	-	-	-

Text-mined citations for rs121434473 ...

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 Aug 25, 2024

ClinVar Genomic variation as it relates to human health

NC_012920.1(MT-TH):m.12183G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434473 ...