rs199476105
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ND6 | unassigned_transcript_4816 | c.215C>T | p.Ala72Val | missense_variant | Exon 1 of 1 | |||
| TRNE | unassigned_transcript_4817 | c.*215C>T | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Leber optic atrophy Pathogenic:3Other:1
- -
- -
This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. -
- -
Leigh syndrome Pathogenic:2Other:1
The variant m.14459G> A (p.Ala72Val) in the MT-ND6 gene is reported as pathogenic for Leigh syndrome and Leber hereditary optic neuropathy (LHON) in ClinVar (Variation ID: 9689) and is cited as pathogenic mutation in MITOMAP. The variant was identified in three out of 51836 sequences of the entire mitochondrial DNA (frequency 0.006%, GenBank, MITOMAP). This variant has previously been reported in patients with phenotypes ranging from Leigh or Leigh-like syndrome to Leber Hereditary Optic Neuropathy (LHON) plus dystonia, pure dystonia, pure LHON, or clinically asymptomatic. Jun et al. (1994) identified the variant m.14459G> A in heteroplasmy in a family with LHON and dystonia. Shoffner et al. (1995) identified the m.14459G> A mutation in a mother and daughter with isolated LHON (the daughter also had unilateral basal ganglia lesions on MRI). Kirby et al. (2000) identified the homoplasmic variant m.14459G> A in 3 patients with Leigh syndrome in whom there was no evidence of LHON or dystonia. Gropman and colleagues (2004) identified the m.14459G> A variant in a family with a broad spectrum of clinical manifestations. The proband presented with anarthria, dystonia, spasticity, and mild encephalopathy; MRI showed symmetrical and bilateral hyperintense lesions in the basal ganglia associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with varying clinical and laboratory characteristics, confirming the heterogeneous phenotype of this mutation even within the same family (OMIM * 516006). -
- -
The NC_012920.1:m.14459G>A (YP_003024037.1:p.Ala72Val) variant in MTND6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP4, PP6 -
Leber optic atrophy and dystonia Pathogenic:1
- -
Leigh syndrome due to mitochondrial complex I deficiency Pathogenic:1
- -
Mitochondrial disease Pathogenic:1
The m.14459G>A (p.A72V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features ranging from Leber Hereditary Optic Neuropathy (LHON) with or without dystonia, Leigh syndrome, bilateral basal ganglia lesions, ataxia, and migraines (PS4; PMIDs: 8016139, 7654063, 16380132, 10894222, 14735584, 21749722, 14735585, 28503604, 32045392, 29408632, 22426787). This variant has been identified as a de novo occurrence in at least 2 probands with primary mitochondrial disease (PM6; PMIDs: 14735584, 10894222). This variant heteroplasmy level segregated with severity in six family members from four families (PP1_moderate; PMIDs: 22426787, 21749722, 7654063, 8016139). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.93 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMID: 8622678). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PP1_moderate, PP3, PS3_supporting. -
not provided Pathogenic:1
- -
MELAS syndrome Pathogenic:1
The variant is observed at an extremely low frequency in the gnomAD v3.1.2 dataset (heteroplasmic allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 8622678). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009689). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 10894222, 14735584). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at