chr1-12001423-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.839G>A(p.Arg280His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R280C) 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 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250290Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135432
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461472Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727024
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2A2 Pathogenic:6
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000002271) and different missense changes at the same codon (p.Arg280Cys, p.Arg280Pro / ClinVar ID: VCV000245809, VCV000801444) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Variant confirmed as disease-causing by referring clinical team -
PM2_supporting: The highest population allele frequency in gnomAD v4.0 is 0.00001160 (0.001%; 1/86188 alleles) in South asian population and 0.000001799 (0.0001%; 2/1111878) in the European non-Finnish population. PP1_strong: variant segregates with =3 informative meioses across =1 family (PMID: 16835246, 16714318, 24957169). PM1 met: variant occurs in the dynamin-like GTPase domain together with other pathogenic variants. PP3_moderate: Revel score is 0.92. PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 17296794, PMID 17215403). PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PM5 met: MFN2 p.Arg280Pro classified as likely pathogenic. -
not provided Pathogenic:4
Published functional studies show that R280H alters mitochondrial fusion (Detmer et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16835246, 22492563, 21149811, 17296794, 31832804, 32657593, 35153971, 30340945, 16714318, 19584314, 17215403, 10732809, 28286897, 27549087, 27863451, 28660751, 24957169, 27027447, 27088055, 30219582, 31211173, 31827005, 15064763, 33136338, 32376792, 35418194, 24863639) -
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The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with Charcot-Marie-Tooth disease and appears to be associated with disease in at least one family. This variant appears to occur de novo in multiple individuals with clinical features associated with Charcot-Marie-Tooth disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant inhibited mitochondrial fusion and caused abnormal clustering (PMID: 17215403, 17296794). The variant is located in a region that is considered important for protein function and/or structure. -
Charcot-Marie-Tooth disease Pathogenic:2
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Peripheral neuropathy Pathogenic:1
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Charcot-Marie-Tooth disease type 2 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 280 of the MFN2 protein (p.Arg280His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 15064763, 16835246, 24957169, 27088055, 27549087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2271). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. Experimental studies have shown that this missense change affects MFN2 function (PMID: 17215403, 17296794). For these reasons, this variant has been classified as Pathogenic. -
Neuropathy, hereditary motor and sensory, type 6A Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at