ClinVar Miner

Submissions for variant NM_005445.3(SMC3):c.1942A>G (p.Met648Val) (rs886041239)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000319826 SCV000329524 pathogenic not provided 2016-08-04 criteria provided, single submitter clinical testing The M648V pathogenic variant in the SMC3 gene has been reported previously as a somatic variant in a head and neck squamous cell carcinoma, but has not been reported in the germline (Stransky et al., 2011). The M648V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M648V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The M648V variant is located within the flexible hinge region of the protein, which is essential for protein function (Gruber et al., 2006). We interpret M648V as a pathogenic variant.
Medical Genetics Lab, Policlinico S. Orsola.Malpighi RCV000721938 SCV000852015 likely pathogenic Intellectual disability 2018-11-09 criteria provided, single submitter clinical testing The Met648Val variant in SMC3 is extremely rare (never reported in GnomAD exomes and genomes) and missense variants of this gene are a known cause of disease. Furthermore, this variant is de novo in the patient and there is no family history of the disease. On the other hand, prediction scores are conflicting (MutationTaster: disease-causing; SIFT: tolerated) and the clinical picture of this patient is not reminiscent of Cornelia de Lange syndrome. We interpret Met648Val as a likely pathogenic variant.

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