rs199476112
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM2PP5_Very_StrongBS2
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
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ND4 | unassigned_transcript_4811 | c.1019G>A | p.Arg340His | missense_variant | Exon 1 of 1 |
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:11Other:2
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A heteroplasmic (76.20%) missense variant has been identified in MT-ND4. This gene encodes a protein subunit of complex I. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 340 of the protein. The arginine at this position has high conservation (MITOMASTER). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, HmtDB Disease Score). The variant is present in the MITOMAP population database at a frequency of 0.358%. The variant has been previously described as pathogenic in multiple individuals with Leber hereditary optic neuropathy (LHON) and is considered to be the most common MT-ND4 variant in European and Asian populations. Affected individuals generally have more than 70% heteroplasmy in blood, however the variant is also known to have reduced penetrance, with males more commonly affected than females (ClinVar, GeneReviews, OMIM, PMID: 31932089). This variant has been shown to be maternally inherited (by trio analysis) with a heteroplamic level of 26.70% in this individual's mother. -
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The NC_012920.1:m.11778G>A (YP_003024035.1:p.Arg340His) variant in MTND4 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS4 -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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This variant is one of the three most common causes of LHON. -
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Criteria applied: PS4,PP1_MOD,PS3_SUP,PP3 -
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not provided Pathogenic:4
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m.11778G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000). It is estimated that 70% of LHON families of northern European descent carry the m.11778G>A variant (Mackey 1996). -
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not specified Pathogenic:1
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Leber optic atrophy and dystonia Pathogenic:1
It is observed in the gnomAD v3.1.2 (https://gnomad.broadinstitute.org) dataset at homoplasmic allele frequency of 0.019% and heteroplasmic allele frequency of 0.023%. Predicted Consequence/Location: Mitochondrial variant. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 10976107, 7763260). In silico tool predictions suggest damaging effect of the variant on gene or gene product (APOGEE 0.9 >=0.5). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009708). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 1635296, 17254817, 17724295, 18216301, 18848389, 2390098, 2566021, 2575667, 25917160, 27119776, 3201231, 8902729). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 2390098, 27119776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Mitochondrial disease Pathogenic:1
The m.11778G>A (p.R340H) variant in MT-ND4 has been reported in >16 unrelated individuals with primary mitochondrial disease. While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, affected individuals have been reported with features including LHON, Leigh syndrome, cerebellar ataxia, migraines, regression, leukoencephalopathy, myoclonus, psychiatric illness, Parkinsonism, axonal neuropathy, multiple sclerosis, and ophthalmoplegia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 3201231, 2575667, 2566021, 2390098, 1635296, 17724295, 18848389, 25917160, 18216301, 17254817, 8902729, 27119776). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 27119776, 2390098). There are no confirmed de novo occurrences of this variant to our knowledge. This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10976107, 7763260). This variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature and/or have reduced penetrance, such as the common variants associated with LHON. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4, PP1_moderate, PP3. -
Optic atrophy Pathogenic:1
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Leber optic atrophy, susceptibility to Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at