ClinVar Miner

Submissions for variant NM_024009.3(GJB3):c.589G>A (p.Val197Ile)

gnomAD frequency: 0.00003  dbSNP: rs376506263
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039323 SCV000063007 likely benign not specified 2013-03-04 criteria provided, single submitter clinical testing Val197Ile variant in exon 2 of GJB3: This variant is not expected to have clinic al significance due to lack of conservation across mammals and distant species. Of note, several mammals including primates (rhesus monkey and baboon) have an i soleucine (Ile) at this position. In addition, computational analyses (biochemic al amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) suggest the vari ant may not impact the protein. This variant has been identified in 1/8600 (0.01 %) European American chromosomes by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757335 SCV000885521 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing The p.Val197Ile variant (rs376506263) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database (Variation ID: 46086). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 11 out of 277,074 chromosomes). The valine at codon 197 is moderately conserved considering 13 species (Alamut software v2.9), and several species including Rhesus macaque have an isoleucine at this position, suggested this variant is evolutionary tolerated. Additionally, computational analyses suggest this variant does not have a significant effect on GJB3protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Val197Ile variant cannot be determined with certainty.
Invitae RCV000757335 SCV003282296 uncertain significance not provided 2022-07-20 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 46086). This variant has not been reported in the literature in individuals affected with GJB3-related conditions. This variant is present in population databases (rs376506263, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 197 of the GJB3 protein (p.Val197Ile).

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