rs199474657

Variant names:

• chrM-3243-A-G
• rs199474657
• unassigned_transcript_4788:c.14A>G

Your query was ambiguous. Multiple possible variants found:

• chrM-3243-A-G
• chrM-3243-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The ENST00000000000(TRNL1):​c.14A>G​(p.Glu5Gly) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002521380: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:30962477)." and additional evidence is available in ClinVar.

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 ENST00000000000 missense
• Scores: Mitotip Uncertain 13
• Clinical Significance: Pathogenic reviewed by expert panel P:44 O:3 MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO
• Conservation: PhyloP100: 5.83
• Publications: 89 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002521380: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30962477).; SCV003921833: Functional studies showed that the variant has a deleterious effect on tRNA structure and function and that this causes defective mitochondrial protein synthesis and reduced mitochondrial energy generation (PMIDs: 10858457, 12101407, 15477592 and 25192935).; SCV004101341: Cybrid studies support the functional impact of this variant (PMID: 1732728).; SCV006557556: Cybrid and single fiber studies support the functional impact of this variant (PMIDs: 18455161, 1378759, 1732728, 8154867, 9741403).
• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-3243-A-G is Pathogenic according to our data. Variant chrM-3243-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9589.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000386347.1. 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-TL1	ENST00000386347.1	TSL:6	n.14A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND1	ENST00000361390.2	TSL:6	c.-64A>G		upstream_gene	N/A	ENSP00000354687.2	P03886
	MT-RNR2	ENST00000387347.2	TSL:6	n.*14A>G		downstream_gene	N/A

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56383

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56383

Alfa AF: 0.0000817 Hom.: 0

Mitomap

Disease(s): MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO

Status: Cfrm-[P],Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
15	-	-	MELAS syndrome (16)
6	-	-	Mitochondrial disease (6)
6	-	-	not provided (6)
3	-	-	Diabetes-deafness syndrome maternally transmitted (3)
1	-	-	3-methylglutaconic aciduria type 1 (1)
1	-	-	Age related macular degeneration 2 (1)
1	-	-	Auditory neuropathy spectrum disorder (1)
1	-	-	Cerebral palsy (1)
1	-	-	Cyclical vomiting syndrome (1)
1	-	-	Histiocytoid cardiomyopathy (1)
1	-	-	Leigh syndrome, mitochondrial (1)
1	-	-	Maternally-inherited mitochondrial myopathy (1)
1	-	-	MELAS syndrome;C0162672:MERRF syndrome (1)
1	-	-	MERRF/MELAS overlap syndrome (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	1.0
PhyloP100		5.8

Other links and lift over

dbSNP: rs199474657; hg19: chrM-3244;