chr1-12002025-A-G
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_014874.4(MFN2):c.1082A>G(p.His361Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H361Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.1082A>G | p.His361Arg | missense_variant | 11/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.1082A>G | p.His361Arg | missense_variant | 11/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 19, 2015 | A novel H361R variant that is likely pathogenic was identified in the MFN2 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The H361R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, this substitution occurs at a position that is highly conserved across species and the H361R variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Furthermore, missense variants in the same residue (H361Y) and in nearby residues (T356A, K357N, T362M, R364W/Q/O, M376L) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at