Clinical Validity Scoring Notes and points | Variant/Case Evidence: PMID: 25351778 Describes 15 new patients (including 1 fetus) with 6q16 deletions, which is the most common variant in patients exhibiting the PWS-like phenotype Investigated using chromosomal microarray analysis All reported 6q16 deletions occurred de novo in symptomatic patients Other genes also included in these deletions (listed in supplemental information)
PMID: 26795956 Performed copy number variation analysis of the 6q14.1–6q16.3 region followed by mutation analysis of SIM1 and MRAP2 in a PWL cohort. p.P352S was identified in a ten-year-old boy presenting with early-onset extreme obesity, intellectual disability and behavior and learning deficits. In addition, the patient shows small hands and feet and an acceleration in bone age. He was clinically diagnosed with PWS although this could not be confirmed molecularly as no aberration on chromosome 15q11.2–q13 was detected with MS-MLPA. Present in 450 hets in gnomAD v4 (FAF 0.0003347). PreventionGenetics ClinVar summary suggests that this variant is benign.
PMID: 23778136 SIM1 sequenced in 44 children with PWS-like features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults p.T46R, p.H323Y, and p.T714A showed strong LOF effects on luciferase gene reporter assays p.I128T Identified in 1 individual with PWL syndrome and one control. Functional studies showed a mild effect on SIM1 activity. Very common in gnomAD v4 (FAF 0.001141), will not score.
p.Q152E Identified in 1 individual with PWL syndrome. Functional studies showed a mild effect on SIM1 activity. Common in gnomAD v4 (FAF 0.0003475), will not score.
p.R581G Identified in 1 individual with PWL syndrome. Functional studies showed no effect on SIM1 activity. Present in 21 hets in gnomAD v4, will not score.
p.T714A Identified in 5 individuals with PWL syndrome and 1 individual that was overweight. Functional studies showed a strong effect on SIM1 activity. Present in 12 hets in gnomAD v4, will not score.
PMID: 24038875 De novo interstitial deletion at 6q16.1–q21 (chr6:98,119,288–107,977,239 (hg18)), that included SIM1 and 30 other genes, was identified in a 12 year old male with Prader–Willi-like syndrome
PMID: 18648397 Report 5 patients with overlapping interstitial 6q16 deletions and Prader–Willi-like phenotype Cases 2 and 3 show heart defects (ductus arteriosus and atrial septal defects in case 2, tetralogy of Fallot in case 3) and are haploinsufficient for the POPDC3 gene
PMID: 12161602 PMID: 23778139 Identified 13 heterozygous variants in SIM1 in 28 unrelated severely obese patients (c.213C>G, c.383T>C, c.454C>G, c.512G>A, c.713T>G, c.1147A>G, c.1490C>G, c.1622C>T, c.1649G>A, c.2075C>T, c.2108G>A, c.2119G>C, 2135C>T) c.383T>C, c.454C>G, and c.2119G>C were also seen in controls Generated stable cell lines expressing the mutant SIM1 proteins and tested their ability to activate the transcription of a SIM1-responsive reporter gene. Of the 13 variants examined, 9 (S71R, R171H, Q152E, I128T, L238R, P497R, R550H, D707H, and T712I) had significantly reduced activity in this assay when paired with the proposed in vivo partner, ARNT2
PMID: 16829351 Other papers on SIM1 and obesity: PMID: 31872862, PMID: 10587584, PMID: 25234154 (obesity and developmental delay), PMID: 33434169 (obesity and hypopituitarism) Segregation Evidence: Case/Control Evidence: Experimental Evidence: Source: |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| No evidence for haploinsufficiency in ClinGen (2012), but there are pLOF variants reported in ClinVar for SIM1-related disorder The literature notes that SIM1 loss of function seems to be associated with obesity and may also be associated with PWL-related clinical features (however there is incomplete penetrance) |