ClinVar Miner

Submissions for variant NM_005445.4(SMC3):c.2567G>C (p.Gly856Ala)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV004547383 SCV005042934 uncertain significance Cornelia de Lange syndrome 3 criteria provided, single submitter clinical testing The missense c.2567G>Cp.Gly856Ala variant in gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes and novel in 1000 Genomes. The amino acid Gly at position 856 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly856Ala in SMC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV004547383 SCV005703782 uncertain significance Cornelia de Lange syndrome 3 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 856 of the SMC3 protein (p.Gly856Ala). This variant is present in population databases (rs745863058, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 3235035). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMC3 protein function with a negative predictive value of 95%. 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.

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