VCV000042226.13 - ClinVar

NC_012920.1(MT-TS1):m.7471dup

Germline

Top reviewed classifications are shown here.

Submission summary:

11 submissions

9 submitters

8 conditions

Reviewed by expert panel

Pathogenic

Nov 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

NC_012920.1(MT-TS1):m.7471dup

Variation ID: 42226 Accession: VCV000042226.13

Type and length

Duplication, 1 bp

Location

MT: 7465-7466 (GRCh38) [ NCBI UCSC ] MT: 7465-7466 (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 25, 2024	Nov 14, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_012920.1:m.7471dup

Protein change

Other names

m.7471_7472insC
C7471CC
7472insC

Canonical SPDI

NC_012920.1:7465:CCCCCC:CCCCCCC

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: CA214937 Genetic Testing Registry (GTR): GTR000591976 OMIM: 590080.0003 dbSNP: rs111033319 Genetic Testing Registry (GTR): GTR000591967 Genetic Testing Registry (GTR): GTR000591975 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-TS1		-	-	GRCh38	29	42

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 cytochrome c oxidase deficiency	Pathogenic (1)	no assertion criteria provided	May 1, 2001	RCV000010178.2
Deafness, sensorineural, with neurologic features	Pathogenic (1)	no assertion criteria provided	May 1, 2001	RCV000022905.2
Mitochondrial non-syndromic sensorineural hearing loss	Pathogenic (2)	no assertion criteria provided	May 1, 2001	RCV000035051.5
MELAS syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2019	RCV000850889.1
Mitochondrial disease	Pathogenic (2)	reviewed by expert panel	Nov 14, 2022	RCV003153328.2
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Oct 4, 2011	RCV000844678.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV001543566.3
Mitochondrial complex IV deficiency, nuclear type 1	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247421.1

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.
Pathogenic (Nov 14, 2022)	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: SCV003842286.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/70c69556-61de-4e88-8de9-ae8b0bcba308 Comment: The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated … (more) The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID: 32906214): PS4, PP1_moderate, PS3_supporting. (less)
Pathogenic (Oct 04, 2011)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Rare genetic deafness (Mitochondrial inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058691.5 First in ClinVar: May 03, 2013 Last updated: Jan 02, 2016	Publications: PubMed (18) PubMed: 7581383‚ 9832034‚ 9708714‚ 10094190‚ 11378827‚ 15292920‚ 15833431‚ 15482956‚ 20064630‚ 9778273‚ 18398437‚ 10545608‚ 18977334‚ 9778262‚ 11919191‚ 16368237‚ 19718780‚ 17637808 Comment: The 7471_7472insC variant in the MTTS1 gene has been reported in 14 probands aff ected with either hearing loss, neurological abnormalities, or both, is absent … (more) The 7471_7472insC variant in the MTTS1 gene has been reported in 14 probands aff ected with either hearing loss, neurological abnormalities, or both, is absent i n 1381 controls, and cosegregates with disease in affected family members (Tiran ti 1995, Ensinke 1998, Jaksch 1998, Verhoeven 1999, Fetoni 2004, Jacobs 2005, Pu lkes 2005, Cardaioli 2006, Leveque 2007, Swalwell 2008, Valente 2009). In additi on, functional analyses of muscle biopsies from affected individuals and in vitr o mitochondrial clones harboring the variant reveal deficiency in COX and defect ive mitochondrial respiration (Tiranti 1995, Jaksch 1998, Fetoni 2004, Pulkes 20 05, Valente 2009). In summary, this variant meets our criteria to be classified as pathogenic. (less) Number of individuals with the variant: 4
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Mitochondrial complex IV deficiency, nuclear type 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517725.1 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	MELAS syndrome Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV000993123.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019	Publications: PubMed (2) PubMed: 31965079‚ 7581383 Comment: The NC_012920.1:m.7471dupC variant in MT-TS1 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.7471dupC variant in MT-TS1 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, PS5 (less)
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Mitochondrial inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762227.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Hearing impairment (present) , Cerebellar ataxia (present) Sex: female
Pathogenic (Jan 20, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Mitochondrial disease Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014700.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (13) PubMed: 9778273‚ 9778262‚ 11378827‚ 10545608‚ 7581383‚ 15833431‚ 15482956‚ 16368237‚ 17637808‚ 9832034‚ 15292920‚ 10094190‚ 9708714 Comment: The MT-TS1 m.7465dup (n.49dup) variant, also referred to as m.7471dup and m.7472insC in the literature, results in the insertion of a nucleotide at position m.7465. … (more) The MT-TS1 m.7465dup (n.49dup) variant, also referred to as m.7471dup and m.7472insC in the literature, results in the insertion of a nucleotide at position m.7465. Across a selection of available literature, this variant has been reported in at least 22 unrelated individuals with primary mitochondrial disease across several haplogroups (PMID: 7581383; 9708714; 9778262; 9778273; 9832034; 10094190; 11378827; 15292920; 15482956; 15833431; 16368237; 17637808). This variant has been associated with isolated sensorineural hearing loss; however, affected individuals can also have other features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebral and cerebellar atrophy, exercise intolerance, and hypotonia. This variant has been seen in affected individuals in homoplasmic and heteroplasmic states. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PMIDs: 9708714; 10094190; 15833431; 16368237). The variant is reported in the Genome Aggregation Database (version 3.1.2) at a homoplasmic frequency of 0.000089 and a heteroplasmic frequency of 0.000462, which may be consistent with reduced penetrance and tissue-specific heteroplasmy of the variant. Cybrid studies supported the functional impact of this variant (PMID: 10545608). Based on the available evidence, the m.7465dup (n.49dup) variant is classified as pathogenic for primary mitochondrial disease. (less)
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199289.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	MITOCHONDRIAL CYTOCHROME c OXIDASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030399.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 9832034‚ 7581383‚ 10094190‚ 10545608‚ 11378827 Comment on evidence: Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase … (more) Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase deficiency associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation. In a Sicilian family with maternally inherited hearing loss as a predominant feature, Tiranti et al. (1995) found the insertion of a C at nucleotide position 7472 of the MTTS1 gene. In 6 of 9 patients, the hearing loss was accompanied by ataxia, dysarthria, and focal myoclonus. Verhoeven et al. (1999) reported a Dutch family with maternally inherited, progressive, sensorineural hearing loss (500008) in 27 patients with the same mutation. They determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leukocyte heteroplasmy. However, in the Dutch family, only a single family member with hearing loss showed accompanying neurologic symptoms including ataxia and dysarthria. Verhoeven et al. (1999) suggested that modifying secondary factors must account for the interfamilial differences in penetrance of the neurologic abnormalities. They concluded, furthermore, that this mutation should be analyzed in patients with maternally inherited hearing loss, irrespective of whether the hearing loss is nonsyndromic or accompanied by neurologic abnormalities. Three members with the 7472insC mutation developed hearing loss after the use of aminoglycosides. For this reason, Verhoeven et al. (1999) analyzed for this mutation in 52 patients who suffered from acute hearing loss after the use of aminoglycosides; 43 of these patients were unrelated. In 7 of the 43, the 1555A-G mutation (561000.0001) in the MTRNR1 gene was found, but the 7472insC mutation was not detected in any of them. This was the third mitochondrial mutation identified as the cause of hearing loss, the others being 1555A-G and 7445A-G (590080.0002), which is also in the MTTS1 gene. Toompuu et al. (1999) performed studies of the 7472insC mutation in osteosarcoma cell cybrids. They found no evidence for a specific defect in aminoacylation, and unlike the case with the np 7445 mutation, which is also associated with deafness, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparison of the np 7472 and np 7445 mutant phenotypes in cultured cells suggested that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA-ser, to which some cells of the auditory system are especially vulnerable. In 6 Western European families with the heteroplasmic 7472insC mutation in the MTTS1 gene, Hutchin et al. (2001) performed mtDNA haplotype analysis on the basis of 10 polymorphic restriction enzyme sites. The families were assigned to haplogroups K, V, and H. There were 4 families in haplogroup H, which is the most common European haplogroup (approximately 40%). Sequence analysis of the D-loop region showed that the 4 haplogroup H families were not closely related, supporting that the 7472insC mutation had occurred multiple times in the European population. The presence of the same mutation on separate mtDNA backgrounds confirmed the notion that the 7472insC mutation alone is sufficient to cause hearing loss and that when present at very high levels can also lead to neurologic dysfunction. (less)
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	DEAFNESS, SENSORINEURAL, WITH NEUROLOGIC FEATURES Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044196.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 9832034‚ 7581383‚ 10094190‚ 10545608‚ 11378827 Comment on evidence: Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase … (more) Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase deficiency associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation. In a Sicilian family with maternally inherited hearing loss as a predominant feature, Tiranti et al. (1995) found the insertion of a C at nucleotide position 7472 of the MTTS1 gene. In 6 of 9 patients, the hearing loss was accompanied by ataxia, dysarthria, and focal myoclonus. Verhoeven et al. (1999) reported a Dutch family with maternally inherited, progressive, sensorineural hearing loss (500008) in 27 patients with the same mutation. They determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leukocyte heteroplasmy. However, in the Dutch family, only a single family member with hearing loss showed accompanying neurologic symptoms including ataxia and dysarthria. Verhoeven et al. (1999) suggested that modifying secondary factors must account for the interfamilial differences in penetrance of the neurologic abnormalities. They concluded, furthermore, that this mutation should be analyzed in patients with maternally inherited hearing loss, irrespective of whether the hearing loss is nonsyndromic or accompanied by neurologic abnormalities. Three members with the 7472insC mutation developed hearing loss after the use of aminoglycosides. For this reason, Verhoeven et al. (1999) analyzed for this mutation in 52 patients who suffered from acute hearing loss after the use of aminoglycosides; 43 of these patients were unrelated. In 7 of the 43, the 1555A-G mutation (561000.0001) in the MTRNR1 gene was found, but the 7472insC mutation was not detected in any of them. This was the third mitochondrial mutation identified as the cause of hearing loss, the others being 1555A-G and 7445A-G (590080.0002), which is also in the MTTS1 gene. Toompuu et al. (1999) performed studies of the 7472insC mutation in osteosarcoma cell cybrids. They found no evidence for a specific defect in aminoacylation, and unlike the case with the np 7445 mutation, which is also associated with deafness, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparison of the np 7472 and np 7445 mutant phenotypes in cultured cells suggested that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA-ser, to which some cells of the auditory system are especially vulnerable. In 6 Western European families with the heteroplasmic 7472insC mutation in the MTTS1 gene, Hutchin et al. (2001) performed mtDNA haplotype analysis on the basis of 10 polymorphic restriction enzyme sites. The families were assigned to haplogroups K, V, and H. There were 4 families in haplogroup H, which is the most common European haplogroup (approximately 40%). Sequence analysis of the D-loop region showed that the 4 haplogroup H families were not closely related, supporting that the 7472insC mutation had occurred multiple times in the European population. The presence of the same mutation on separate mtDNA backgrounds confirmed the notion that the 7472insC mutation alone is sufficient to cause hearing loss and that when present at very high levels can also lead to neurologic dysfunction. (less)
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044197.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 9832034‚ 7581383‚ 10094190‚ 10545608‚ 11378827 Comment on evidence: Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase … (more) Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase deficiency associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation. In a Sicilian family with maternally inherited hearing loss as a predominant feature, Tiranti et al. (1995) found the insertion of a C at nucleotide position 7472 of the MTTS1 gene. In 6 of 9 patients, the hearing loss was accompanied by ataxia, dysarthria, and focal myoclonus. Verhoeven et al. (1999) reported a Dutch family with maternally inherited, progressive, sensorineural hearing loss (500008) in 27 patients with the same mutation. They determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leukocyte heteroplasmy. However, in the Dutch family, only a single family member with hearing loss showed accompanying neurologic symptoms including ataxia and dysarthria. Verhoeven et al. (1999) suggested that modifying secondary factors must account for the interfamilial differences in penetrance of the neurologic abnormalities. They concluded, furthermore, that this mutation should be analyzed in patients with maternally inherited hearing loss, irrespective of whether the hearing loss is nonsyndromic or accompanied by neurologic abnormalities. Three members with the 7472insC mutation developed hearing loss after the use of aminoglycosides. For this reason, Verhoeven et al. (1999) analyzed for this mutation in 52 patients who suffered from acute hearing loss after the use of aminoglycosides; 43 of these patients were unrelated. In 7 of the 43, the 1555A-G mutation (561000.0001) in the MTRNR1 gene was found, but the 7472insC mutation was not detected in any of them. This was the third mitochondrial mutation identified as the cause of hearing loss, the others being 1555A-G and 7445A-G (590080.0002), which is also in the MTTS1 gene. Toompuu et al. (1999) performed studies of the 7472insC mutation in osteosarcoma cell cybrids. They found no evidence for a specific defect in aminoacylation, and unlike the case with the np 7445 mutation, which is also associated with deafness, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparison of the np 7472 and np 7445 mutant phenotypes in cultured cells suggested that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA-ser, to which some cells of the auditory system are especially vulnerable. In 6 Western European families with the heteroplasmic 7472insC mutation in the MTTS1 gene, Hutchin et al. (2001) performed mtDNA haplotype analysis on the basis of 10 polymorphic restriction enzyme sites. The families were assigned to haplogroups K, V, and H. There were 4 families in haplogroup H, which is the most common European haplogroup (approximately 40%). Sequence analysis of the D-loop region showed that the 4 haplogroup H families were not closely related, supporting that the 7472insC mutation had occurred multiple times in the European population. The presence of the same mutation on separate mtDNA backgrounds confirmed the notion that the 7472insC mutation alone is sufficient to cause hearing loss and that when present at very high levels can also lead to neurologic dysfunction. (less)
not provided (-)	no classification provided Method: literature only	Mitochondrial non-syndromic sensorineural hearing loss Affected status: unknown Allele origin: maternal	GeneReviews Accession: SCV000914176.2 First in ClinVar: May 20, 2019 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 20301595‚ 10094190‚ 15292920 BookShelf: NBK1422 BookShelf: NBK1422
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Comment:

The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID: 32906214): PS4, PP1_moderate, PS3_supporting.

Comment:

The 7471_7472insC variant in the MTTS1 gene has been reported in 14 probands aff ected with either hearing loss, neurological abnormalities, or both, is absent i n 1381 controls, and cosegregates with disease in affected family members (Tiran ti 1995, Ensinke 1998, Jaksch 1998, Verhoeven 1999, Fetoni 2004, Jacobs 2005, Pu lkes 2005, Cardaioli 2006, Leveque 2007, Swalwell 2008, Valente 2009). In additi on, functional analyses of muscle biopsies from affected individuals and in vitr o mitochondrial clones harboring the variant reveal deficiency in COX and defect ive mitochondrial respiration (Tiranti 1995, Jaksch 1998, Fetoni 2004, Pulkes 20 05, Valente 2009). In summary, this variant meets our criteria to be classified as pathogenic.

Comment:

The MT-TS1 m.7465dup (n.49dup) variant, also referred to as m.7471dup and m.7472insC in the literature, results in the insertion of a nucleotide at position m.7465. Across a selection of available literature, this variant has been reported in at least 22 unrelated individuals with primary mitochondrial disease across several haplogroups (PMID: 7581383; 9708714; 9778262; 9778273; 9832034; 10094190; 11378827; 15292920; 15482956; 15833431; 16368237; 17637808). This variant has been associated with isolated sensorineural hearing loss; however, affected individuals can also have other features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebral and cerebellar atrophy, exercise intolerance, and hypotonia. This variant has been seen in affected individuals in homoplasmic and heteroplasmic states. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PMIDs: 9708714; 10094190; 15833431; 16368237). The variant is reported in the Genome Aggregation Database (version 3.1.2) at a homoplasmic frequency of 0.000089 and a heteroplasmic frequency of 0.000462, which may be consistent with reduced penetrance and tissue-specific heteroplasmy of the variant. Cybrid studies supported the functional impact of this variant (PMID: 10545608). Based on the available evidence, the m.7465dup (n.49dup) variant is classified as pathogenic for primary mitochondrial disease.

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
Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations.	Nishigaki Y	Mitochondrion	2010	PMID: 20064630
Pathogenic mitochondrial tRNA mutations--which mutations are inherited and why?	Elson JL	Human mutation	2009	PMID: 19718780
Identification of novel mutations in five patients with mitochondrial encephalomyopathy.	Valente L	Biochimica et biophysica acta	2009	PMID: 18977334
A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: are two mutations better than one?	Swalwell H	European journal of human genetics : EJHG	2008	PMID: 18398437
Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip.	Lévêque M	European journal of human genetics : EJHG	2007	PMID: 17637808
Rapidly progressive neurodegeneration in a case with the 7472insC mutation and the A7472C polymorphism in the mtDNA tRNA ser(UCN) gene.	Cardaioli E	Neuromuscular disorders : NMD	2006	PMID: 16368237
New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation.	Pulkes T	Neuromuscular disorders : NMD	2005	PMID: 15833431
Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment.	Jacobs HT	European journal of human genetics : EJHG	2005	PMID: 15292920
Monomelic amyotrophy associated with the 7472insC mutation in the mtDNA tRNASer(UCN) gene.	Fetoni V	Neuromuscular disorders : NMD	2004	PMID: 15482956
The 7472insC mitochondrial DNA mutation impairs the synthesis and extent of aminoacylation of tRNASer(UCN) but not its structure or rate of turnover.	Toompuu M	The Journal of biological chemistry	2002	PMID: 11919191
Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction.	Hutchin TP	European journal of human genetics : EJHG	2001	PMID: 11378827
Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids.	Toompuu M	Human molecular genetics	1999	PMID: 10545608
Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene.	Verhoeven K	European journal of human genetics : EJHG	1999	PMID: 10094190
A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy.	Jaksch M	Journal of medical genetics	1998	PMID: 9832034
Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation.	Schuelke M	Annals of neurology	1998	PMID: 9778273
Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene.	Jaksch M	Annals of neurology	1998	PMID: 9778262
Early-onset sensorineural hearing loss and late-onset neurologic complaints caused by a mitochondrial mutation at position 7472.	Ensink RJ	Archives of otolaryngology--head & neck surgery	1998	PMID: 9708714
Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene.	Tiranti V	Human molecular genetics	1995	PMID: 7581383
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/70c69556-61de-4e88-8de9-ae8b0bcba308	-	-	-	-
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Text-mined citations for rs111033319 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NC_012920.1(MT-TS1):m.7471dup

Variant Details

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Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033319 ...