rs373211062
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_014874.4(MFN2):c.1101G>C(p.Gln367His) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q367P) has been classified as Pathogenic.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFN2 | NM_014874.4 | c.1101G>C | p.Gln367His | missense_variant | 11/19 | ENST00000235329.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFN2 | ENST00000235329.10 | c.1101G>C | p.Gln367His | missense_variant | 11/19 | 1 | NM_014874.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000236 AC: 36AN: 152258Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251496Hom.: 1 AF XY: 0.0000736 AC XY: 10AN XY: 135922
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 727246
GnomAD4 genome ? AF: 0.000236 AC: 36AN: 152258Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74390
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MFN2 related disorder (PMID:33415332, PS1_P). A different missense change at the same codon (p.Gln367Pro) has been reported to be associated with MFN2 related disorder (PMID:26801520, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.841, PP3_P). A missense variant is a common mechanism associated with Charcot-Marie-Tooth disease (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000103, PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 05, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | The p.Q367H variant (also known as c.1101G>C), located in coding exon 9 of the MFN2 gene, results from a G to C substitution at nucleotide position 1101. The glutamine at codon 367 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie-Tooth disease, axonal, type 2A2A and/or hereditary motor and sensory neuropathy VIA; however, its contribution to the development of Charcot-Marie-Tooth disease, axonal, type 2A2B is uncertain. - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at