ClinVar Miner

Submissions for variant NM_006306.3(SMC1A):c.3146G>A (p.Arg1049Gln) (rs587784416)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255003 SCV000322272 pathogenic not provided 2016-12-20 criteria provided, single submitter clinical testing The R1049Q variant in the SMC1A gene has been reported previously as a de novo change in an individual with Cornelia de Lange syndrome (Liu et al., 2009). The R1049Q variant was not observed in approximately 6500 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 R1049Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. The R1049Q variant maps to the coiled-coil domain, which may interfere with heterodimer formation and disrupt the interaction with other cohesin subunits (Mannini et al., 2010). We interpret R1049Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000147564 SCV000195012 likely pathogenic Congenital muscular hypertrophy-cerebral syndrome 2013-08-30 criteria provided, single submitter clinical testing
Invitae RCV000147564 SCV000637995 uncertain significance Congenital muscular hypertrophy-cerebral syndrome 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1049 of the SMC1A protein (p.Arg1049Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Cornelia de Lange syndrome (PMID: 19701948). ClinVar contains an entry for this variant (Variation ID: 159954). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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