ClinVar Miner

Submissions for variant NM_001303256.3(MORC2):c.1181A>G (p.Tyr394Cys) (rs1555938796)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624267 SCV000742758 uncertain significance Inborn genetic diseases 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
GeneDx RCV000498431 SCV000589765 likely pathogenic not provided 2016-02-23 criteria provided, single submitter clinical testing The Y332C variant in the MORC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y332C variant 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 Y332C 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The Y332C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000689169 SCV000816809 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2z 2018-05-10 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 332 of the MORC2 protein (p.Tyr332Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot–Marie–Tooth disease (CMT)  (PMID: 28771897). ClinVar contains an entry for this variant (Variation ID: 432089). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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