ClinVar Miner

Submissions for variant NM_000127.3(EXT1):c.1781C>G (p.Ala594Gly)

gnomAD frequency: 0.00003  dbSNP: rs374887549
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001165074 SCV001327241 likely benign Multiple congenital exostosis 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.
Invitae RCV001165074 SCV003259706 uncertain significance Multiple congenital exostosis 2023-05-21 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. 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 not expected to disrupt EXT1 protein function. ClinVar contains an entry for this variant (Variation ID: 912089). This variant has not been reported in the literature in individuals affected with EXT1-related conditions. This variant is present in population databases (rs374887549, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 594 of the EXT1 protein (p.Ala594Gly).

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