M-7497-G-A

Position:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_SupportingPM2PS3_SupportingPP1_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The m.7497G>A variant in MT-TS1 has been reported in three unrelated individuals with primary mitochondrial disease with shared features of exercise intolerance, proximal myopathy, lactic acidosis, and myalgia. Age at presentation ranged from three years old to the 30s. Muscle biopsies showed ragged red fibers, COX-negative fibers, and reduced activities of complexes I and IV. All probands were homoplasmic for the variant in muscle and it was present in various other tissues at levels >90%. (PS4_supporting; PMIDs: 14605505, 9778262). This variant segregated with disease in each of the three families reported (PP1_moderate). The probands were homoplasmic for the variant muscle and/or blood. In one family, the unaffected mother harbored the variant at 10% in blood (PMID:14605505). In the second family, the unaffected mother harbored the variant at 62% and the unaffected brother had the variant at 62% in blood (PMID:9778262). In the third family, an affected daughter with myalgia had the variant at 90% in blood and an unaffected brother has the variant at 70% (PMID:9778262). There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (92.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activities (PS3_supporting, PMID:16199753). 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, PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CV9569/MONDO:0044970/014

Frequency

Mitomap GenBank:
Absent

Consequence

MT-TS1
ENST00000387416.2 non_coding_transcript_exon

Scores

Mitotip
Pathogenic
18

Clinical Significance

Likely pathogenic reviewed by expert panel P:4
MM-/-EXIT

Conservation

PhyloP100: 0.128
Variant links:
Genes affected
MT-TS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))
MT-TD (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
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/exons MANE Protein UniProt
TRNS1TRNS1.1 use as main transcriptn.18C>T non_coding_transcript_exon_variant 1/1
TRNDTRND.1 use as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MT-TS1ENST00000387416.2 linkuse as main transcriptn.18C>T non_coding_transcript_exon_variant 1/1
MT-TDENST00000387419.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.0
AC:
0
AN:
56429
Gnomad heteroplasmic
AF:
0.000035
AC:
2
AN:
56429

Mitomap

MM-/-EXIT

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Exercise intolerance, muscle pain, and lactic acidemia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2003- -
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenApr 17, 2023The m.7497G>A variant in MT-TS1 has been reported in three unrelated individuals with primary mitochondrial disease with shared features of exercise intolerance, proximal myopathy, lactic acidosis, and myalgia. Age at presentation ranged from three years old to the 30s. Muscle biopsies showed ragged red fibers, COX-negative fibers, and reduced activities of complexes I and IV. All probands were homoplasmic for the variant in muscle and it was present in various other tissues at levels >90%. (PS4_supporting; PMIDs: 14605505, 9778262). This variant segregated with disease in each of the three families reported (PP1_moderate). The probands were homoplasmic for the variant muscle and/or blood. In one family, the unaffected mother harbored the variant at 10% in blood (PMID: 14605505). In the second family, the unaffected mother harbored the variant at 62% and the unaffected brother had the variant at 62% in blood (PMID: 9778262). In the third family, an affected daughter with myalgia had the variant at 90% in blood and an unaffected brother has the variant at 70% (PMID: 9778262). There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (92.9 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activities (PS3_supporting, PMID: 16199753). 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, PS3_supporting, PM2_supporting, PP3. -
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineJul 12, 2019The NC_012920.1:m.7497G>A 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
18
Hmtvar
Pathogenic
0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387906419; hg19: chrM-7498; API