Submissions for variant NM_005068.3(SIM1):c.2119G>C (p.Asp707His)

gnomAD frequency: 0.00058  dbSNP: rs74726213

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482527	SCV000568356	uncertain significance	not provided	2021-07-31	criteria provided, single submitter	clinical testing	Reported in individuals with severe obesity, food-seeking behavior, and/or neurodevelopmental features, and was inherited from both obese and non-obese parents (Swarbick et al., 2011; Ramachandrappa et al., 2013); Published functional studies demonstrate decreased transcriptional activation (Ramachandrappa et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25234154, 21512513, 2152513, 28299356, 23778139)
Illumina Laboratory Services, Illumina	RCV001158265	SCV001319885	uncertain significance	Obesity due to SIM1 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174498	SCV001337637	uncertain significance	Monogenic diabetes	2017-07-14	criteria provided, single submitter	research	ACMG criteria: PP3 (5 predictors), BP4 (5 predictors); ClinVar with conflicting evidence (Montreal calls LB, GeneDx calls VUS); PS3 (reduced transcriptional activation PMID: 23778139)=VUS
Genetic Services Laboratory, University of Chicago	RCV001820794	SCV002069782	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518552	SCV003629292	likely benign	Inborn genetic diseases	2022-11-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482527	SCV004247878	likely benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
CHU Sainte-Justine Research Center, University of Montreal	RCV000240299	SCV000299177	likely benign	Oromandibular-limb hypogenesis spectrum	2016-08-12	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004547625	SCV004106772	uncertain significance	SIM1-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The SIM1 c.2119G>C variant is predicted to result in the amino acid substitution p.Asp707His. This variant was reported to be associated with severe obesity with incomplete penetrance based on its occurrence in seven affected subjects from four unique families. However, it was also detected in four control individuals (Table S1, Ramachandrappa et al. 2013. PubMed ID: 23778139). In another study, the p.Asp707His variant was also described in one individual with obesity (Swarbrick et al. 2011. PubMed ID: 21512513). In addition, the ability of the SIM1 transcription factor to drive expression of a reporter transgene was decreased to less than 60% of wild type in cells harboring the p.Asp707His variant (Ramachandrappa et al. 2013. PubMed ID: 23778139). However, this variant is reported in 0.095% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than other known or suspected pathogenic variants in SIM1. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.