rs199474821

Variant names:

• chrM-7511-T-C
• rs199474821
• unassigned_transcript_4800:c.4A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PP3 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The m.7511T>C variant in MT-TS1 has been reported in ten unrelated probands from ten kindreds of varying ethnic background with nonsyndromic sensorineural hearing loss (PS4_moderate; PMIDs: 10371545, 12461693, 15670746, 18340555, 26279247, 25968158, 28320335, 29257206). In these families, the variant is present in family members with and without hearing loss. Hearing loss was variable overall when present, ranging from mild to profound. Age of onset of hearing loss varied from childhood to adulthood. Hearing loss was stable in some individuals and progressive in others. Some individuals also reported tinnitus and vertigo. There has been no other organ system involvement reported to date (although it is not clear if other organ systems were assessed in affected individuals). Muscle biopsy was not routinely performed in affected individuals however one individual did have COX-deficient fibers and complex IV deficiency (PMID:10371545). The variant was generally present at homoplasmy (in maternal family members with and without hearing loss), however there were some heteroplasmic occurrences (PMIDs: 10371545, 12461693, 15670746, 26279247, 29257206). Penetrance differed across reported families, and several modifying factors were discussed, including variants in the genes PCDH15 (PMID:26279247) and YARS2 (PMID:25968158). Affected and unaffected individuals in these families had the variant and there was no correlation between severity and heteroplasmy level, thus preventing consideration for PP1. There are no de novo occurrences of this variant reported to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (78.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Single fiber testing (PMID:10371545) and cybrid analysis (PMID:14960712) support the pathogenicity of this variant (PS3_moderate), as do other functional assays performed (PMIDs: 31685661, 16361254). This variant meets criteria to be classified as of uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340922/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS1 unassigned_transcript_4800 missense
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 SNHL/Deafness
• Conservation: PhyloP100: 4.90
• Publications: 1 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS1	unassigned_transcript_4800	c.4A>G	p.Lys2Glu	missense_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-75T>C		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-7T>C		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*66T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.4A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CO2	ENST00000361739.1	c.-75T>C		upstream_gene_variant		6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*66T>C		downstream_gene_variant		6		ENSP00000354499.2
MT-TD	ENST00000387419.1	n.-7T>C		upstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56429

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56429

Mitomap

Disease(s): SNHL/Deafness

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Nov 30, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.7511T>C variant in MT-TS1 has been reported in ten unrelated probands from ten kindreds of varying ethnic background with nonsyndromic sensorineural hearing loss (PS4_moderate; PMIDs: 10371545, 12461693, 15670746, 18340555, 26279247, 25968158, 28320335, 29257206). In these families, the variant is present in family members with and without hearing loss. Hearing loss was variable overall when present, ranging from mild to profound. Age of onset of hearing loss varied from childhood to adulthood. Hearing loss was stable in some individuals and progressive in others. Some individuals also reported tinnitus and vertigo. There has been no other organ system involvement reported to date (although it is not clear if other organ systems were assessed in affected individuals). Muscle biopsy was not routinely performed in affected individuals however one individual did have COX-deficient fibers and complex IV deficiency (PMID: 10371545). The variant was generally present at homoplasmy (in maternal family members with and without hearing loss), however there were some heteroplasmic occurrences (PMIDs: 10371545, 12461693, 15670746, 26279247, 29257206). Penetrance differed across reported families, and several modifying factors were discussed, including variants in the genes PCDH15 (PMID: 26279247) and YARS2 (PMID: 25968158). Affected and unaffected individuals in these families had the variant and there was no correlation between severity and heteroplasmy level, thus preventing consideration for PP1. There are no de novo occurrences of this variant reported to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (78.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. Single fiber testing (PMID: 10371545) and cybrid analysis (PMID: 14960712) support the pathogenicity of this variant (PS3_moderate), as do other functional assays performed (PMIDs: 31685661, 16361254). This variant meets criteria to be classified as of uncertain significance however this Expert Panel elected to modify the classification to likely pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common mitochondrial variants associated with nonsyndromic hearing loss. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PP3. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MELAS syndrome Pathogenic:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.7511T>C 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, PM7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.75
PhyloP100		4.9

Other links and lift over

dbSNP: rs199474821; hg19: chrM-7512;