ClinVar Miner

Submissions for variant NM_153717.3(EVC):c.928C>G (p.Leu310Val) (rs145300726)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657891 SCV000779654 likely pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The L310V variant in the EVC gene has been reported in trans with another pathogenic variant in association with Ellis-van Creveld syndrome (D'Asdia et al., 2013). The L310V variant is not observed in large population cohorts (Lek et al., 2016). The L310V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses predict that this variant creates a cryptic splice donor site 12 base pairs upstream of the natural splice donor site of exon 7. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000665471 SCV000789601 uncertain significance Ellis-van Creveld syndrome 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000689940 SCV000817612 likely pathogenic Ellis-van Creveld syndrome; Curry-Hall syndrome 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 310 of the EVC protein (p.Leu310Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs145300726, ExAC 0.004%). This variant has been observed in individuals affected with Ellis-van Creveld syndrome (PMID: 23220543, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 546095). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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