ClinVar Miner

Submissions for variant NM_005068.2(SIM1):c.2119G>C (p.Asp707His) (rs74726213)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHU Sainte-Justine Research Center,University of Montreal RCV000240299 SCV000299177 likely benign Oromandibular-limb hypogenesis spectrum 2016-08-12 no assertion criteria provided research
GeneDx RCV000482527 SCV000568356 uncertain significance not provided 2017-03-15 criteria provided, single submitter clinical testing The D707H variant in the SIM1 gene has been reported previously in the heterozygous state in multiple unrelated individuals with severe, early onset obesity, food-seeking behavior, and neurodevelopmental features, and was inherited from both obese and non-obese parents, thus demonstrating variable penetrance (Ramachandrappa et al., 2013). Although the D707H variant was also identified in controls, functional studies indicate the D707H variant results in reduced activity (Ramachandrappa et al., 2013). In addition, the D707H variant was also reported in a severely obese individual, but further details were not provided (Swarbrick et al., 2011). The D707H variant is observed in 57/66736 (0.09%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The D707H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D707H as a variant of uncertain significance.

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