ClinVar Miner

Submissions for variant NM_014314.4(RIGI):c.1232C>T (p.Ser411Leu)

gnomAD frequency: 0.00001  dbSNP: rs267602206
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
New York Genome Center RCV001837279 SCV002097799 uncertain significance Singleton-Merten syndrome 2 2021-02-11 criteria provided, single submitter clinical testing The inherited c.1232C>T (p.Ser411Leu) missense variant at the conserved DEAD box helicase domain in exon 9 of 18 of DDX58 has not been reported in affected individuals in the available literature, though functional studies for this variant was reported in a single publication [PMID: 28180316]. The variant is absent in gnomADv3 and seen at a very low frequency in gnomaAD v2 (2 heterozygotes, allele frequency=7.96e-6, no homozygotes) indicating it is not a common benign variant in the populations represented in this databases. In silico predictors suggest this variant is Damaging (Provean; score:-5.83; SIFT; score:0). Given the lack of evidence supporting its pathogenicity, the c.1232C>T (p.Ser411Leu) variant identified in the DDX58 gene is reported as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003772357 SCV004681622 uncertain significance not provided 2023-10-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 411 of the DDX58 protein (p.Ser411Leu). This variant is present in population databases (rs267602206, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DDX58-related conditions. ClinVar contains an entry for this variant (Variation ID: 1341799). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DDX58 protein function. Experimental studies have shown that this missense change affects DDX58 function (PMID: 28180316). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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