ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.1142G>A (p.Arg381His)

dbSNP: rs281865137
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000701335 SCV000830132 pathogenic Charcot-Marie-Tooth disease, type I 2023-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 381 of the EGR2 protein (p.Arg381His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg381 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been observed in individuals with EGR2-related conditions (PMID: 11239949, 20513111), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects EGR2 function (PMID: 12609493). 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 EGR2 protein function. ClinVar contains an entry for this variant (Variation ID: 41008). This missense change has been observed in individual(s) with Charcot-Marie-Tooth (CMT) (PMID: 10762521, 12471219, 22765307, 25720245). In at least one individual the variant was observed to be de novo.
CMT Laboratory, Bogazici University RCV000033901 SCV001548306 pathogenic Charcot-Marie-Tooth disease type 1D 2020-12-01 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002472942 SCV002771698 pathogenic not provided 2021-08-12 criteria provided, single submitter clinical testing This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies have shown that this variant results in the loss of transcriptional regulatory activity required for normal myelination (PMID: 11734543, 12609493).
CeGaT Center for Human Genetics Tuebingen RCV002472942 SCV004125463 pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing EGR2: PM1, PM2, PM5, PM6, PS4:Moderate, PS3:Supporting
GeneReviews RCV000033901 SCV000057815 not provided Charcot-Marie-Tooth disease type 1D no assertion provided literature only
Inherited Neuropathy Consortium RCV000789745 SCV000929123 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Genesis Genome Database RCV000789745 SCV000999523 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Inherited Neuropathy Consortium Ii, University Of Miami RCV000033901 SCV004174370 uncertain significance Charcot-Marie-Tooth disease type 1D 2016-01-06 no assertion criteria provided literature only

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