chrM-7497-G-A

Position:

• chrM-7497-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_Supporting PM2 PS3_Supporting PP1_Moderate PP3

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

Genes affected

MT-TS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

TRNS1 (HGNC:):

MT-TD (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

ACMG classification

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
TRNS1	TRNS1.1	n.18C>T		non_coding_transcript_exon_variant	1/1
TRND	TRND.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.18C>T		non_coding_transcript_exon_variant	1/1
MT-TD	ENST00000387419.1			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

Submissions by phenotype

Exercise intolerance, muscle pain, and lactic acidemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2003

- -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Apr 17, 2023

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. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 12, 2019

The 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

Other links and lift over

dbSNP: rs387906419; hg19: chrM-7498;