ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.707C>T (p.Thr236Met) (rs773159585)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201150 SCV000255684 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2013-01-29 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414991 SCV000493019 likely pathogenic Distal muscle weakness; Peripheral axonal neuropathy; Distal lower limb amyotrophy 2014-06-04 criteria provided, single submitter clinical testing
Invitae RCV000470638 SCV000547920 likely pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 236 of the MFN2 protein (p.Thr236Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases at a very low frequency (rs773159585, ExAC <0.01%). This variant has been reported in individual(s) affected with Charcot-Marie-Tooth disease (PMID: 15549395, Invitae). This variant has also been reported to segregate with disease in an affected family (PMID: 25403865). ClinVar contains an entry for this variant (Variation ID: 217165). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In addition, algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare missense change that has been reported in individuals affected with CMT2 and that segregates with disease in an affected family. For these reasons, this variant has been classified as Likely Pathogenic.
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong RCV001257085 SCV001364385 likely pathogenic not provided 2020-06-02 criteria provided, single submitter research By the ACMG guideline 2015, this variant is classified as likely pathogenic (PM1, PM2, PP2, PP3) with multiple affected individuals reported. Our patient does not habour typical features of Charcot Marie Tooth disease or neuropathy. Rather, he presented with other neurological issues such as intellectual disability, behavioural problems and seizure.
Genesis Genome Database RCV000857096 SCV000999669 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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