ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.494A>G (p.His165Arg) (rs863224970)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201063 SCV000255683 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2015-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000235729 SCV000293528 pathogenic not provided 2016-05-20 criteria provided, single submitter clinical testing The H165R missense variant in the MFN2 gene has been reported previously in association with CMT2 (Chung et al., 2006; Verhoeven et al., 2006; Cho et al., 2007; Bergamin et al., 2014; Choi et al., 2015; Chung et al., 2010). Additionally, different amino acid substitutions at this same position (H165Y/L) have been reported in association with CMT (Stenson et al., 2014), and the H165 residue has been reported as a mutation hotspot (Cho et al., 2007). H165R was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H165R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, it alters a highly conserved position in the GTPase domain where many other missense variants have been reported in association with CMT (Stenson et al., 2014).
Invitae RCV000653851 SCV000775741 pathogenic Charcot-Marie-Tooth disease, type 2 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 165 of the MFN2 protein (p.His165Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease (CMT) in 2 families (PMID: 16835246) and has also been reported in several individuals affected with CMT (PMID: 16714318, 24819634, 17309650). ClinVar contains an entry for this variant (Variation ID: 217164). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.His165Tyr, p.His 165Asp, p.His165Leu) have been reported in individuals affected with CMT (PMID: 16087932, 24126688, 27549087, 20951041, 16714318). This suggests that the histidine residue is critical for MFN2 protein function and that other missense substitutions at this position may be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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