ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.457A>C (p.Thr153Pro) (rs202183386)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540413 SCV000636230 likely benign Charcot-Marie-Tooth disease, type I 2020-01-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001108766 SCV001266038 likely benign Charcot-Marie-Tooth disease, demyelinating, type 1d 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356784 SCV001552046 uncertain significance not provided no assertion criteria provided clinical testing The EGR2 p.Thr103Pro variant was not identified in the literature but was identified in dbSNP (ID: rs202183386) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 53 of 282632 chromosomes at a frequency of 0.0001875 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 41 of 10358 chromosomes (freq: 0.003958), Other in 1 of 7216 chromosomes (freq: 0.000139), European (non-Finnish) in 10 of 129006 chromosomes (freq: 0.000078) and African in 1 of 24938 chromosomes (freq: 0.00004), but was not observed in the Latino, East Asian, European (Finnish), or South Asian populations. The p.Thr103 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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