ClinVar Miner

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

dbSNP: rs1555938796
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498431 SCV000589765 pathogenic not provided 2021-09-17 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34189813, 28771897, 32693025, 33098801)
Ambry Genetics RCV000624267 SCV000742758 uncertain significance Inborn genetic diseases 2018-01-10 criteria provided, single submitter clinical testing
Invitae RCV000689169 SCV000816809 pathogenic Charcot-Marie-Tooth disease axonal type 2Z 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 394 of the MORC2 protein (p.Tyr394Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MORC2-related conditions (PMID: 28771897, 32693025). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MORC2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000689169 SCV001149839 pathogenic Charcot-Marie-Tooth disease axonal type 2Z 2018-04-18 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003983095 SCV004800531 pathogenic MORC2-related condition 2024-02-17 criteria provided, single submitter clinical testing The MORC2 c.1181A>G variant is predicted to result in the amino acid substitution p.Tyr394Cys. This variant was reported in individuals with neurodevelopmental disorders or suspected Charcot-Marie-Tooth disease; in several, this variant arose de novo (see, for example, Guillen Sacoto et al. 2020. PubMed ID: 32693025; Zech et al. 2020. PubMed ID: 33098801, supplementary data, reported as p.Tyr332Cys; Sivera et al. 2021. PubMed ID: 34189813; Frongia et al. 2021. PubMed ID: 34630290). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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