Submissions for variant NM_001303256.3(MORC2):c.260C>T (p.Ser87Leu) (rs864309504)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522454	SCV000618293	pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The S87L variant in the MORC2 gene has been reported previously, using alternate nomenclature S25L, as a de novo variant in individuals with infantile onset Charot-Marie-Tooth disease (Sevilla et al., 2016; Hyun et al., 2016). The S87L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S87L 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. We interpret S87L as a pathogenic variant.
Invitae	RCV000202460	SCV000655836	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2z	2018-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 25 of the MORC2 protein (p.Ser25Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in multiple individuals affected with Charcot-Marie-Tooth disease type 2 (CMT2) (PMID: 26497905, 27105897). ClinVar contains an entry for this variant (Variation ID: 218308). 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: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000202460	SCV000257500	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2z	2015-10-24	no assertion criteria provided	literature only
Genesis Genome Database	RCV000857126	SCV000999704	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research

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