1-11999009-G-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_014874.4(MFN2):c.730G>A(p.Val244Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V244A) has been classified as Uncertain significance.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.730G>A | p.Val244Met | missense_variant | 8/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.730G>A | p.Val244Met | missense_variant | 8/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2A2 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | This variant has been previously reported as disease-causing and was found in one patient with demyelinating neuropathy and one patient with axonal neuropathy - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 01, 2019 | For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Val244Leu) has been determined to be likely pathogenic (PMID: 26378787, 26257172). This suggests that the valine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 15549395, 20008656). This variant has also been shown to be de novo in affected individuals (PMID: 26257172, Invitae). ClinVar contains an entry for this variant (Variation ID: 243066). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 244 of the MFN2 protein (p.Val244Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at