ClinVar Miner

Submissions for variant NM_001303256.3(MORC2):c.79G>A (p.Glu27Lys)

dbSNP: rs1602510200
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000991068 SCV001134974 pathogenic not provided 2022-03-21 criteria provided, single submitter clinical testing Reported in the literature as a de novo finding in an individual with a neurodevelopmental disorder, however, additional clinical information was not included (Deciphering Developmental Disorders Study, 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135719, 32693025)
Revvity Omics, Revvity RCV000991068 SCV002017526 pathogenic not provided 2020-08-10 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001796981 SCV002038546 pathogenic MORC2-related neurodevelopmental disorders 2021-05-28 criteria provided, single submitter clinical testing The MORC2 c.79G>A (p.Gly27Lys) variant is a missense variant that has been reported in one study, in which it was found to occur de novo in a heterozygous state in five individuals with a neurodevelopmental phenotype including developmental delays and intellectual disability, and variably hearing loss, microcephaly, short stature, facial dysmorphisms, retinopathy, and abnormalities on brain MRI (Guillen Sacoto et al. 2020). The variant was also reported in a de novo state in one individual with developmental delay in the Deciphering Developmental Disorders Study, detailed clinical information was not available (Deciphering Developmental Disorders Study, 2017). The p.Gly27Lys variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, so the variant is presumed to be rare. In vitro genetic complementation experiments in MORC2-deficient cells demonstrated the p.Gly27Lys variant resulted in hyperactivation of HUSH-mediated epigenetic silencing (Guillen Sacoto et al. 2020). Based on the collective evidence and application of the ACMG criteria, the p.Gly27Lys variant is classified as pathogenic for MORC2-related neurodevelopmental disorders.
3billion RCV001281381 SCV002058146 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MORC2 related disorder (ClinVar ID: VCV000804164). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32693025, PS3_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 32693025, PS2_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.949, PP3_P). A missense variant is a common mechanism associated with Developmental delay (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mendelics RCV002249596 SCV002517628 pathogenic Charcot-Marie-Tooth disease axonal type 2Z 2022-05-04 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272381 SCV002557556 pathogenic Neurodevelopmental disorder 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2Z (MIM#616688), and Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (MIM#619090) (PMID: 32693025). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Histidine kinase-like ATPase domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent de novo variant reported in multiple individuals with neurodevelopmental disorders with growth retardation and variable craniofacial dysmorphism (ClinVar, Decipher, PMID: 32693025). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant resulted in hyperactivation of epigenetic silencing by the HUSH complex (PMID: 32693025). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (21G000768, 21G000769). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center RCV001281381 SCV002576423 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2022-08-15 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3, PS4_MOD, PM2_SUP, PP3
Breda Genetics srl RCV001281381 SCV002586266 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2022-06-29 criteria provided, single submitter clinical testing The variantc.79G>A (p.Glu27Lys) in the MORC2 gene is reported as pathogenic for neurodevelopmental disorders MORC2-related in ClinVar (Variation ID: 806144) and in LOVD database v.3.0. Sacoto et al. (2020, PMID:32693025) reported this variant in the heterozygous state in five patient with psychomotor retardation, developmental delay and intellectual disability. This variant has also been found in another study (Deciphering Developmental Disorders Study, 2017, PMID: 28135719), in a patient with developmental delay, but without any additional clinical sign reported in the article (PMID:28135719). The variant has not been reported in dbSNP, gnomAD, 1000 Genomes Project or ClinVar.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001281381 SCV002762861 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2022-12-15 criteria provided, single submitter clinical testing
Invitae RCV002249596 SCV003461811 pathogenic Charcot-Marie-Tooth disease axonal type 2Z 2022-11-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MORC2 function (PMID: 32693025). 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. ClinVar contains an entry for this variant (Variation ID: 804164). This missense change has been observed in individual(s) with clinical features of MORC2-related conditions (PMID: 32693025). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 27 of the MORC2 protein (p.Glu27Lys).
Ambry Genetics RCV002549755 SCV003561188 pathogenic Inborn genetic diseases 2021-07-30 criteria provided, single submitter clinical testing The c.79G>A (p.E27K) alteration is located in coding exon 2 of the MORC2 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the glutamic acid (E) at amino acid position 27 to be replaced by a lysine (K). Based on data from the Genome Aggregation Database (gnomAD), the MORC2 c.79G>A alteration was not observed, with coverage at this position. This alteration has been reported de novo in multiple patients affected with developmental delay, intellectual disability, microcephaly, and variable brain MRI and retinal anomalies (Guillen Sacoto, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.E27K alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003432987 SCV004117104 pathogenic MORC2-related disorder 2022-08-23 criteria provided, single submitter clinical testing The MORC2 c.79G>A variant is predicted to result in the amino acid substitution p.Glu27Lys. This variant has been reported to occur de novo in multiple unrelated individuals with MORC2-related disorders (Supplementary Table 1 in McRae et al. 2017. PubMed ID: 28135719; Guillen Sacoto et al. 2020. PubMed ID: 32693025). Consistent with this, functional studies demonstrate the c.79G>A (p.Glu27Lys) variant exerts a hyperactivating effect on HUSH-mediated transcriptional silencing (Guillen Sacoto et al. 2020. PubMed ID: 32693025). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Multiple clinical diagnostic laboratories have interpreted this variant as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/804164). Based on the available evidence, we classify this variant as pathogenic.
OMIM RCV001281381 SCV001468677 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2021-01-11 no assertion criteria provided literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001281381 SCV001738749 pathogenic Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy 2020-01-01 no assertion criteria provided clinical testing

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