rs199474667

Variant names:

• chrM-3249-G-A
• rs199474667
• unassigned_transcript_4788:c.20G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3249G>A variant in MT-TL1 has been reported in one individual to date, in a man with progressive vision loss, hearing loss, myopathy, and ragged red and COX-negative fibers, whose presentation was reminiscent of Kearns Sayre syndrome (PMID:11448301). The variant was present at 85% heteroplasmy in skeletal muscle and 45% in leukocytes in the proband, 5% in the blood of the healthy mother, and was undetectable in blood from a healthy sister (PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 39.3%; HmtVAR: 0.45). There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID:20550934) and RNAseP binding interference (PMID:33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID:33380464; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254840/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 unassigned_transcript_4788 missense
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 KSS
• Conservation: PhyloP100: 6.34
• Publications: 2 publications found

Genes affected

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS3: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL1	unassigned_transcript_4788	c.20G>A	p.Gly7Asp	missense_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-58G>A		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*20G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.20G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-58G>A		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*20G>A		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): KSS

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Apr 22, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.3249G>A variant in MT-TL1 has been reported in one individual to date, in a man with progressive vision loss, hearing loss, myopathy, and ragged red and COX-negative fibers, whose presentation was reminiscent of Kearns Sayre syndrome (PMID: 11448301). The variant was present at 85% heteroplasmy in skeletal muscle and 45% in leukocytes in the proband, 5% in the blood of the healthy mother, and was undetectable in blood from a healthy sister (PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 39.3%; HmtVAR: 0.45). There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting. -

Kearns-Sayre syndrome Uncertain:1

Jun 11, 2010

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.45
PhyloP100		6.3

Other links and lift over

dbSNP: rs199474667; hg19: chrM-3250;