ClinVar Miner

Submissions for variant NM_006306.3(SMC1A):c.2368C>T (p.Arg790Trp) (rs587784412)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147560 SCV000195008 pathogenic Congenital muscular hypertrophy-cerebral syndrome 2014-05-01 criteria provided, single submitter clinical testing
Invitae RCV000147560 SCV000760987 likely pathogenic Congenital muscular hypertrophy-cerebral syndrome 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 790 of the SMC1A protein (p.Arg790Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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: 25125236). ClinVar contains an entry for this variant (Variation ID: 159950). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg790Gln) has been determined to be pathogenic (PMID: 17273969, 25125236). This suggests that the arginine residue is critical for SMC1A protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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