ClinVar Miner

Submissions for variant NM_014140.4(SMARCAL1):c.2290C>T (p.Arg764Trp)

gnomAD frequency: 0.00001  dbSNP: rs1480919035
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000586742 SCV000693913 uncertain significance Schimke immuno-osseous dysplasia 2017-06-26 criteria provided, single submitter research No reports in the literature identified for this variant. Seen as homozygous variant in 1 case in CMG with nephrotic syndrome. PM2: rare in reference population databases with AC=1 in gnomAD. PP3: In silico predicts damaging.
Labcorp Genetics (formerly Invitae), Labcorp RCV000586742 SCV001383926 likely pathogenic Schimke immuno-osseous dysplasia 2021-06-06 criteria provided, single submitter clinical testing This variant has been observed in individual(s) with clinical features of Schimke immuno-osseous dysplasia or steroid-resistant nephrotic syndrome (PMID: 28796785, 29127259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495338). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 764 of the SMARCAL1 protein (p.Arg764Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg764 amino acid residue in SMARCAL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11799392, 22998683, 18974355, 18805831). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Yale Center for Mendelian Genomics, Yale University RCV001849404 SCV002107057 likely pathogenic Nephrotic syndrome 2017-11-10 no assertion criteria provided literature only

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