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

Total submissions: 2

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.