ClinVar Miner

Submissions for variant NM_001303256.3(MORC2):c.394C>T (p.Arg132Cys) (rs1064795559)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480527 SCV000571490 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The R132C variant in the MORC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, this variant has been observed in the heterozygous state in other individuals with features of a MORC2-related disorder referred for testing at GeneDx. The R132C variant is not observed in large population cohorts (Lek et al., 2016). The R132C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A missense variant in the same residue (R70L per alternate nomenclature) has been reported in association with Charcot-Marie-Tooth disease type 2Z, supporting the functional importance of this region of the protein (Hyun et al., 2016). We interpret R132C as a pathogenic variant.
Invitae RCV000818851 SCV000959485 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2z 2018-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 70 of the MORC2 protein (p.Arg70Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MORC2-related disease. ClinVar contains an entry for this variant (Variation ID: 422103). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000818851 SCV001141406 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2z 2019-05-28 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000991213 SCV001142592 likely pathogenic MORC2-related developmental disorder 2019-06-11 criteria provided, single submitter clinical testing
OMIM RCV001281382 SCV001468678 pathogenic DEVELOPMENTAL DELAY, IMPAIRED GROWTH, DYSMORPHIC FACIES, AND AXONAL NEUROPATHY 2021-01-11 no assertion criteria provided literature only

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