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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387416.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TS1	ENST00000387416.2	TSL:6	n.4A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-75T>C		upstream_gene	N/A	ENSP00000354876.1
	MT-CO1	ENST00000361624.2	TSL:6	c.*66T>C		downstream_gene	N/A	ENSP00000354499.2

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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)

Computational scores

Source: dbNSFP v4.9

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;