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

dbSNP: rs1064795559

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480527	SCV000571490	pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Guillen Sacoto et al., 2020); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28135719, 31785789, 34664855, 34189813, 32693025, 31618753)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818851	SCV000959485	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 70 of the MORC2 protein (p.Arg70Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MORC2-related conditions (PMID: 28135719, 31618753, 31785789, 32693025). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 422103). 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%. Experimental studies have shown that this missense change affects MORC2 function (PMID: 32693025). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000818851	SCV001141406	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2023-12-19	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
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374919	SCV001572206	pathogenic	Neurodevelopmental disorder	2021-02-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271511	SCV002555616	uncertain significance	not specified	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: MORC2 c.394C>T (p.Arg132Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248824 control chromosomes. c.394C>T has been reported in the literature as a de-novo variant among individuals with severe, undiagnosed developmental disorders, Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism, MORC2-related disorder (example, Deciphering Developmental Disorders Study_2017, Turner_2019, Guillen Sacato_2020, Ziats_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories, the Undiagnosed Diseases Network and OMIM have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001281382	SCV003803786	pathogenic	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2022-01-18	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001281382	SCV003807678	likely pathogenic	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2022-11-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001281382	SCV004099201	pathogenic	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2023-07-10	criteria provided, single submitter	clinical testing	PS2, PS4, PM2, PP2, PP3
PreventionGenetics, part of Exact Sciences	RCV003409664	SCV004114084	pathogenic	MORC2-related disorder	2023-06-06	criteria provided, single submitter	clinical testing	The MORC2 c.394C>T variant is predicted to result in the amino acid substitution p.Arg132Cys. This variant has been previously reported as a recurrent de novo variant in several individuals with MORC2-related developmental disorder (Table 1, Guillen Sacoto et al. 2020. PubMed ID: 32693025; Supplementary Table 1, McRae et al. 2017. PubMed ID: 28135719). This variant was also reported in the heterozygous state (inheritance unknown) in an individual with developmental delays, microcephaly, hearing loss, and growth hormone deficiency (Patient 93, Supplementary Tables, Ziats et al. 2020. PubMed ID: 31618753). 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.
OMIM	RCV001281382	SCV001468678	pathogenic	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2021-01-11	no assertion criteria provided	literature only