ClinVar Miner

Submissions for variant NM_145207.3(SPATA5):c.1877G>C (p.Trp626Ser) (rs375343753)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489560 SCV000577344 likely pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing The c.1877G>C variant in the SPATA5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1877G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.1877G>C may strengthen a cryptic splice acceptor site for intron 10 that could supplant the natural splice acceptor site. However, in the absence of RNA/functional studies, the actual effect of the c.1877G>C change in this individual is unknown. If c.1877G>C does not alter splicing, it will result in the W626S missense change. The W626S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The c.1877G>C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000489560 SCV000610754 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Invitae RCV000689945 SCV000817617 uncertain significance Epilepsy, hearing loss, and mental retardation syndrome 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 626 of the SPATA5 protein (p.Trp626Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs375343753, ExAC 0.003%). This variant has not been reported in the literature in individuals with a SPATA5-related disease. ClinVar contains an entry for this variant (Variation ID: 426803). 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 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000489560 SCV000892398 likely pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing

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