SMC1A |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- SMC1A (HGNC:11111) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- structural maintenance of chromosomes 1A
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- SMC1L1
- Alias symbols
- DXS423E, KIAA0178, SB1.8, Smcb
- %HI
- 14.23(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 1(Read more about gnomAD pLI score)
- LOEUF
- 0.06(Read more about gnomAD LOEUF score)
- Cytoband
- Xp11.22
- Genomic Coordinates
-
GRCh37/hg19: chrX:53401070-53449677 NCBI Ensembl UCSC GRCh38/hg38: chrX:53374149-53422728 NCBI Ensembl UCSC - MANE Select Transcript
- NM_006306.4 ENST00000322213.9 (Read more about MANE Select)
- Function
- Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Haploinsufficiency (HI) Score Details
- Cornelia de Lange syndrome 2 Monarch
-
PUBMED:
24896178
Gilissen et al. 2014. In an effort to find molecular causes of extensive genetic heterogeneity of ID, author did WGS on 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. As a result, a total of 84 coding de novo mutation were identified and confirmed by Sanger, including a fs variant (c.2364delC aka p.Asn788Lysfs*fs10) and a 2.1 kb deletion involving exon 16 [resulting in p.(Leu808Argfs*6)] in the female Probands from trio 13 and trio 48 respectively. Both de novo changes are considered the molecular diagnosis for the patients ( Note: the patient with de novo fs variant also had 3 other de novo missense variants in 3 other genes of unknown function). Jansen S et. al. 2016 further presented the detailed phenotype of these two females. And by combining these 2 patients with the other recently reported females carrying SMC1A LoF mutations, the author ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet, considered a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.
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PUBMED:
26386245
Goldstein et al. 2015. Reported two unrelated girls who had developmental delay and medically refractory seizures, with either mild or absent classic CdLS facial features and unrevealing initial laboratory, imaging and genetic evaluations. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. Author also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. (Note: each patient also has 2 other variants in other genes, however they are either heterozygous for an recessive condition or homozygous for a variant of unknown clinical significant for an recessive condition. And parental testing were not performed for these variants)
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PUBMED:
28166369
Ten female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. All presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. These mutations are likely to be nonviable in males.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.
Triplosensitivity (TS) Score Details
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.