ClinVar Miner

Submissions for variant NM_001127207.2(SMARCAL1):c.2542G>T (p.Glu848Ter) (rs119473033)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000004388 SCV000427357 pathogenic Schimke immunoosseous dysplasia 2017-04-27 criteria provided, single submitter clinical testing The SMARCAL1 c.2542G>T (p.Glu848Ter) variant is a stop gained variant and is predicted to result in premature truncation of the protein. The p.Glu848Ter variant has been reported in at least seven studies in which it is found a total of 28 individuals with Schimke immunoosseous dysplasia, including 11 in a homozygous state and 17 in a compound heterozygous state (Boerkoel et al. 2002; Clewing et al. 2007a; Clewing et al. 2007b; Zivicnjak et al. 2009; Zieg et al. 2011; Santangelo et al. 2014; Sanyal et al. 2015). The p.Glu848Ter variant has also been reported in a heterozygous state in nine unaffected parents (Boerkoel et al. 2002; Zieg et al. 2011; Santangelo et al. 2014). The variant was absent from 126 control chromosomes but is reported at a frequency of 0.00045 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Glu848Ter variant results in undetectable protein levels, protein mislocalization, and deficient ATP hydrolyzation (Elizondo et al. 2009). Based on the potential impact of stop-gained variants and the collective evidence, the p.Glu848Ter variant is classified as pathogenic for Schimke immunoosseous dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415311 SCV000493052 pathogenic Atrioventricular septal defect; Short stature; Focal segmental glomerulosclerosis; Microcephaly; Small for gestational age; Disproportionate short-trunk short stature; Decreased body weight; Congenital microcephaly; Steroid-resistant nephrotic syndrome 2014-03-04 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000004388 SCV000693893 pathogenic Schimke immunoosseous dysplasia 2017-06-26 criteria provided, single submitter research PVS1: The c.2542G>T (p.Glu848Ter) variant is a stop gained variant and is predicted to result in premature truncation of the protein. The p.Glu848Ter variant has been reported many times in patients (PMID: 24589093, PMID: 11799392). Functional studies showed that the p.Glu848Ter variant results in undetectable protein levels, protein mislocalization, and deficient ATP hydrolyzation (PMID: 18805831). PM2: Rare in reference population databases, gnomAD AC = 24 (Finnish AF = 0.02%).
Invitae RCV000004388 SCV000760100 pathogenic Schimke immunoosseous dysplasia 2018-11-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu848*) in the SMARCAL1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs119473033, ExAC 0.05%). This variant has been reported in several homozyous and compound heterozygous individuals affected with Schimke-immuno-osseous dysplasia (PMID: 22998683, 26499378, 28796785, 11799392, 18805831, 15880370, 19127206). ClinVar contains an entry for this variant (Variation ID: 4171). Loss-of-function variants in SMARCAL1 are known to be pathogenic (PMID: 11799392, 20301550). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004388 SCV000024560 pathogenic Schimke immunoosseous dysplasia 2009-01-01 no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000004388 SCV000691649 likely pathogenic Schimke immunoosseous dysplasia no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000004388 SCV000863926 pathogenic Schimke immunoosseous dysplasia 2018-08-21 no assertion criteria provided clinical testing

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