ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.227T>C (p.Leu76Pro) (rs28940293)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200837 SCV000251708 pathogenic not provided 2017-09-05 criteria provided, single submitter clinical testing The L76P missense variant in the MFN2 gene has been reported previously in a family with CMT2A characterized by severe distal weakness and atrophy with mild distal sensory loss, proximal muscle strength was reported as normal and the age of onset ranged from 7 to 44 years (Pericak-Vance et al., 1997; Zuchner et al., 2004). Subsequently, the L76P variant has been reported as a common pathogenic variant in individuals with Charcot-Marie-Tooth (DiVincenzo et al., 2014). Functional studies suggest the L76P variant results in mitochondrial aggregation and altered mitochondrial mobility (Baloh et al., 2007; Bergamin et al., 2016). It 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 L76P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. Missense variants in nearby residues (Q74R, G80V) have been reported in the Human Gene Mutation Database in association with CMT2A (Stenson et al., 2014). Therefore, the presence of L76P is consistent with the diagnosis of a MFN2-related disorder
Athena Diagnostics Inc RCV000200837 SCV000255678 pathogenic not provided 2014-12-17 criteria provided, single submitter clinical testing
Invitae RCV000653847 SCV000775737 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 76 of the MFN2 protein (p.Leu76Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant Charcot-Marie-Tooth disease (CMT), type 2A in a single family (PMID: 15064763, 10732809). Additionally, this variant has been reported in an individual affected with CMT (PMID: 16714318) and in individuals who underwent genetic testing for CMT (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 2270). Experimental studies have shown that this missense change prevents the mitofusion 2 protein from properly trafficking mitochondria, leading to mitochondrial aggregates (PMID: 17215403 17296794, 20335458). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000200837 SCV000856104 pathogenic not provided 2017-08-28 criteria provided, single submitter clinical testing
OMIM RCV000002358 SCV000022516 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2004-05-01 no assertion criteria provided literature only

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