Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No curations for this GDA in ClinGen/GenCC

HGMD reports 7 variants in SIM1 associated with Prader-Willi-like syndrome (6 gross deletions and 1 missense from 2 publications)

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

• Identified a 6q16.1-q21 deletion in a patient with a Prader-Willi-like phenotype

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

• Screening for the SIM1 gene deletion performed on 87 patients with PWS-like phenotype, also describe the fifth case of syndromic obesity with an interstitial deletion of the chromosome segment 6q16-q21

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:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

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)

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link