ClinVar Miner

Submissions for variant NM_014140.3(SMARCAL1):c.2290C>T (p.Arg764Trp) (rs1480919035)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute 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.
Invitae RCV000586742 SCV001383926 likely pathogenic Schimke immuno-osseous dysplasia 2020-10-06 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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. 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. 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.

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